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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Fabry disease &#40;FD&#44; OMIM <a href="omim:301500">301500</a>&#41; is one of the lysosomal deposit diseases &#40;LDD&#41;&#46; This group of diseases includes at least 50 hereditary entities of low frequency&#44; originated by a congenital error of the metabolism secondary to a specific monogenic defect that results in a deficiency in the activity of a lysosomal enzyme&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">1</span></a> This enzyme deficiency causes the accumulation of not metabolized substrates primarily in the lysosomes and then&#44; progressively&#44; in other cellular compartments&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In FD&#44; since the fetal stages of life&#44; the absence or the reduced activity of enzyme-galactosidase-A &#40;&#945;-gal-A&#44; EC 3&#46;2&#46;1&#46;22&#41; produces the multisystemic accumulation of glycosphingolipids&#44; mainly globotriaosylceramide &#40;Gb3&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The reported incidence of FD is in the range of one case per 476&#44;000 to one case per 117&#44;000 live births in the general population&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a> although neonatal screening in Italy and Taiwan have reported higher results&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">3&#44;4</span></a> Studies of prevalence report FD exist in 0&#46;33&#37; in men and 0&#46;1&#37; in women with end-stage renal disease &#40;ESRD&#41; of unknown etiology&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Abnormal deposition of non-metabolized substrate affects virtually all tissues and organs&#44; but it is more predominant in the endothelium and smooth muscle cells of blood vessels&#44; along with renal epithelial cells&#44; cardiomyocytes and neural cells&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a> The lysosomal storage of Gb3 produces a cascade of deleterious phenomena among which are the compromise of energy metabolism&#44; the injury of small vessels&#44; the dysfunction of ion channels in endothelial cells&#44; the increase of oxidative stress&#44; the alterations of autophagy&#44; tissue ischemia and fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The globotriaocilesfingosina &#40;Lyso-Gb3&#41;&#44; product of the abnormal metabolism of Gb3&#44; is elevated in patients with FD&#46; Among its recognized effects are&#58; &#40;a&#41; inhibition of enzymatic activity &#945;-gal-A&#59; &#40;b&#41; the release of chemical mediators of glomerular damage&#44; and &#40;c&#41; stimulation of vascular proliferation&#44; with thickening of the intima-media&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">7&#8211;9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In the kidney&#44; progressive deposits of Gb3 affect tubular&#44; glomerular &#40;including podocytes&#41;&#44; endothelial and vascular smooth muscle cells&#46; This has been demonstrated in renal biopsies of patients even without clinical manifestations of kidney involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The first symptoms of EF are expressed during childhood&#44; with acroparesthesias&#44; episodes of neuropathic pain in all four limbs&#44; hypohydrosis&#44; recurrent abdominal pain&#44; diarrhea&#44; nausea and early satiety&#44; and angiokeratomas&#46; During adolescence&#44; cornea verticillata&#44; dysautonomic manifestations and decreased hearing ability&#46; Upon adulthood&#44; renal&#44; cardiac and cerebrovascular disease develops&#44; with increased morbidity and mortality and a decrease in life expectancy as compared with the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Until the year 2001&#44; renal failure was described as the main cause of death in the FD&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">12</span></a> Subsequently&#44; it was reported that the main cause of death is cardiovascular &#40;57&#37; of cases&#41;&#44; that patients dying from cardiovascular causes had previously received dialysis therapy and have had a late diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">13</span></a> For this reason&#44; the research work of nephropathy in patients with FD&#44; its mechanisms&#44; evolution and treatment&#44; has been a topic of relevance among experts&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">14&#8211;20</span></a> Early detection of nephropathy is important because specific treatments for FD are more effective in early stages of kidney damage&#44; decreasing its effectiveness in advanced stages of CKD&#44; mainly due to the development of fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">6&#44;21</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The nephropathy of FD has been studied with both molecular and tissue biomarkers&#44;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">17&#44;22&#8211;24</span></a> which have advantages and disadvantages for use in routine practice&#46; The scarce accessibility of highly complex methods in some geographical areas and the complications of invasive methods make it difficult for the use in routine clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">25</span></a> The purpose of this paper is to describe the role of the nephrologist in the early diagnosis of FD and the clinical variables associated with nephropathy in affected patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">Cross-sectional design with retrospective data collection&#46; Preliminary data of the present study have been previously published&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">26</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The study was approved by each local ethics committee&#46; The patients of legal age&#44; with inclusion criteria&#44; signed the informed consent&#46; The minors gave their consent&#44; and the informed consent was signed by their tutor or legal representative in accordance with local regulations&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Patients with probable diagnosis of FD from June 2007 to September 2017 were recruited from three reference centers in Argentina&#58; &#40;a&#41; Neurosciences Center Los Manantiales&#44; Grupo Gamma Rosario&#44; Rosario&#44; Province of Santa Fe&#59; &#40;b&#41; Infusion Center and Study of Lysosomal Diseases of the Pergamino Clinical Nephrology Institute&#44; Pergamino&#44; Province of Buenos Aires&#44; and &#40;c&#41; Intensive Therapy Service of Dr&#46; Enrique Erill de Escobar Hospital&#44; Bel&#233;n de Escobar&#44; Province of Buenos Aires&#46; Patients included had diagnosis of FD confirmed by genetic study and enzyme dosage &#945;-gal-A were&#46; Exclusion criteria&#58; patients with nephropathy of other etiology different from FD&#46; Criteria for elimination&#58; patients with inclusion criteria who refuse to participate in the study or who present a complication related to the extraction of blood or with diagnostic studies during its execution&#46; Pathogenic mutations of the GLA gene were detected by genetic study&#44; by direct sequencing and Multiplex ligation-dependent probe amplification &#40;MLPA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">27&#44;28</span></a> The measurement of &#945;-gal-A activity was performed by fluorometric method&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">29</span></a> and was considered normal or decreased if it was above and below 4&#46;0<span class="elsevierStyleHsp" style=""></span>nmol&#47;h&#47;l respectively&#46; Creatinine in plasma and urine was determined by electro-chemiluminescence Roche Diagnostics&#46; The eGFR was calculated using the Schwartz equation and the CKD-EPI in patients under and over 21 years of age&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">30&#44;31</span></a> The Kidney Disease classification was used to stage the eGFR&#58; Improving Global Outcomes Chronic Kidney Disease Guideline 2013 &#40;KDIGO&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">32</span></a> Albuminuria was determined by the Roche Diagnostics colorimetric method&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">33</span></a> The albumin&#47;creatinine ratio in urine was used to estimate the urinary excretion of proteins in 24<span class="elsevierStyleHsp" style=""></span>h&#46; Values from 0 to 30 were considered normal&#44; from 30 to 300 microalbuminuria and greater than 300 albuminuria&#44; in at least two urine samples&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">33</span></a> The nephropathy in adults was defined by&#58; &#40;a&#41; microalbuminuria or albuminuria&#44; and&#47;or &#40;b&#41; GFR less than 90<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; and&#47;or &#40;c&#41; the history of kidney function replacement therapy by dialysis or transplant&#46; The nephropathy in pediatric patients was defined by the presence of microalbuminuria or albuminuria&#59; the changes in eGFR were not considered due to the limitations of the calculation of the eGFR in pediatric patients with formulas that use serum creatinine&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">34</span></a> The proportion of index cases diagnosed by a specialist in nephrology was determined&#46; We used the classic definitions of cardiovascular risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">35</span></a> Peripheral nervous system &#40;PNS&#41; involvement was considered due to the presence of neuropathic pain typical of FD or alterations of the quantitative sensory testing &#40;QST&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">36</span></a> Gastrointestinal involvement was established by the presence of abdominal pain&#44; recurrent diarrhea&#44; nausea or early satiety in relation to intake without any other cause than FD&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;37</span></a> The cornea verticilata was evidenced by ophthalmological examination with a slit lamp&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;38</span></a> The angiokeratomas were evaluated by a dermatologist with experience in FD&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a> The auditory abnormalities were evaluated by logo-audiometry&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a> The cardiac involvement was differentiated into&#58; &#40;a&#41; arrhythmias&#44; and &#40;b&#41; structural cardiomyopathy&#44; since both alterations occurred in pediatric and adult patients&#46; Arrhythmias were defined by the presence of electrophysiological alterations in electrocardiogram &#40;12 leads ECG&#41;&#46; Structural heart disease was defined by the presence of LV hypertrophy in color Doppler echocardiography and&#47;or typical images in magnetic nuclear resonance &#40;MRI&#41; with gadolinium&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;39</span></a> The involvement of the central nervous system &#40;CNS&#41; was defined by the history of Stroke and&#47;or typical images in asymptomatic brain MRI&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;40</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Dependent variable&#58; nephropathy&#46; Independent variables&#58; gender&#44; age&#44; &#945;-gal-A activity&#44; peripheral neuropathy&#44; gastrointestinal compromise&#44; cornea verticilata&#44; angiokeratomas&#44; auditory alterations&#44; arrhythmias&#44; structural heart disease&#44; CNS compromise&#44; hypertension &#40;HTN&#41; and smoking&#46; The odds ratio was calculated for the two variables considered risk factors for nephropathy in patients with FD&#58; &#945;-gal-A activity&#44; HTA&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">15&#44;41</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">The data was processed on a SPSS statistics 20 database</span><p id="par0070" class="elsevierStylePara elsevierViewall">To determine the association between the dependent variable and independent variables &#40;nominal variables&#41;&#44; the chi-square test was used with data organized in contingency tables&#46; No Yates correction factor was used since sample was greater than 40&#44; nor exact Fisher test for expected frequencies greater than 5&#46; We worked with a 95&#37; confidence interval&#46; For the calculation of <span class="elsevierStyleItalic">P</span>&#44; the chi-square distribution table was used according to the degree of freedom&#46; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 values were considered of statistical significance to reject the null hypothesis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">A total of 72 patients with a confirmed diagnosis of PE were studied &#40;26&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;5 years&#41;&#44; 30 &#40;41&#46;6&#37;&#41; were men&#46; There were 27 &#40;37&#46;5&#37;&#41; pediatric patients and 45 &#40;62&#46;5&#37;&#41; adults&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We found 13 genotypes&#58; E398X&#44; L415P&#44; M296V&#44; L106R&#44; R227Q&#44; A292T&#44; C&#46;448&#46;delG&#44; R363H&#44; C382Y&#44; R301Q&#44; D109G&#44; from 3 and 4 exons&#44; W81X&#44; all pathogenic mutations of the GLA gene&#46; We studied 14 patients that were &#8220;index case&#8221;&#58; 12 men and 2 women&#44; all adults&#46; A 50&#37; of them were diagnosed by a nephrologist&#44; 14&#46;5&#37; by a cardiologist&#44; 14&#46;5&#37; by a dermatologist&#44; and the rest&#44; 7&#37; by each specialty&#58; neurology&#44; rheumatology and geneticist&#46; The frequency distribution is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; Of the 12 male index cases&#44; 11 patients presented kidney damage &#40;5 patients had ESRD&#41;&#46; The two index case women did not present kidney damage&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">All of the index cases presented the classic phenotype of the disease&#44; the typical early manifestations of childhood were seen in 100&#37; of them&#46; The prevalence of major events typical of adulthood in FD in the index cases group was as follows&#58; &#40;a&#41; one patient &#40;6&#46;00&#37;&#41; presented a major event&#59; &#40;b&#41; 7 patients &#40;46&#46;6&#37;&#41; presented two major events&#44; and &#40;c&#41; 6 patients &#40;40&#46;0&#37;&#41; had three major events&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Nephropathy was found in 44 patients &#40;61&#46;1&#37;&#41;&#58; 6 pediatric patients and 38 adults&#46; The mean eGFR in the pediatric population was 115&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#46;8<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; and in adults&#44; 80&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>42&#46;2<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the frequency distribution of nephropathy according to the KDIGO stage&#46; 100&#37; of patients in stages G3&#44; G4 and G5 were male&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Smoking and hypertension were the only cardiovascular risk factors present in the study population&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows whether there is a significant relationship between patients with or without nephropathy &#40;dependent variable&#41; and a series of descriptive &#40;independent&#41; clinical variables&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the odds ratio values calculated for the exposure factors for the dependent variable &#40;nephropathy&#41;&#58; decreased &#945;-gal-A&#44; HBP and smoking&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">Nephropathy is one of the major complications in FD&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">26</span></a> It is characterized by proteinuria and a progressive decrease in the eGFR&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;26</span></a> The decrease in eGFR over time is directly related to the degree of proteinuria and&#44; without therapeutic intervention&#44; is more pronounced in patients with an initial eGFR of less than 60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">15</span></a> In our population&#44; 18&#37; of the patients presented eGFR less than 60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> at the time of diagnosis&#46; HTA and male sex have been described as risk factors for nephropathy in patients with EF&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">15</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Due to the progression of nephropathy in FD&#44; the affected men presented with ESRD requiring renal replacement therapy at the mean age of 42 years<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">14</span></a> which coincides with the age of inclusion in dialysis of all our patients with ESRD&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In FD nephropathy it is assumed that the initial damage is produced by the abnormal deposit of non-metabolized substrate&#44; Gb3 and its metabolites&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;20</span></a> This leads to a cascade of events that include the compromise of energy metabolism&#44; the injury of small vessels&#44; the dysfunction of ion channels in endothelial cells&#44; the increase of oxidative stress&#44; the alterations of autophagy&#44; ischemia and its final result&#44; tissue fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">2&#44;6&#44;20</span></a> The plasma concentration Lyso-Gb3&#44; the main metabolite of Gb3&#44; is able to induce induces autocrine TGF-&#946;1 and Notch-1 signals in podocytes&#44; similar to the podocyte response to high glucose levels&#44;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">8&#44;42</span></a> signals that also lead to renal fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">6</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Enzyme replacement therapy is the only specific treatment for FD that has been shown to reverse the accumulation of Gb3 in renal tissue&#44; including podocytes&#44; in a dose-dependent manner&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">43</span></a> Its efficacy is greater if stated early&#44; due to the impossibility of correcting the progression when irreversible lesions such as fibrosis are present&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">6&#44;21&#44;44</span></a> Pharmacological chaperones have shown significant histological changes in capillary interstitial cells&#44; but not in podocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">45</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Renal fibrosis has been demonstrated in patients with normal renal function and without albuminuria&#44;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">10&#44;11&#44;16</span></a> and both molecular and histological biomarkers have been studied in prealbuminuric stages of FD nephropathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">8&#44;10&#44;11&#44;16&#44;17&#44;22&#8211;24</span></a> The high complexity and cost of some of the non-invasive methods and the complications of invasive procedures make routine use difficult&#44; so we propose a model that may be valid to predict the association between clinical variables associated with nephropathy and that helps in the early detection of kidney damage in affected patients&#44; through the simple association of clinical data&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In the natural evolution of FD&#44; there is a progressive multisystemic tissue deposition of Gb3&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a> This concept coincides with the results found in our study&#44; in which there was significant association between nephropathy and the age of the patients&#46; In the early stages of tissue damage&#44; patients remain asymptomatic&#44; until substrate deposits and tissue damage reach a critical level and clinical manifestations occur due to organic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a> Two types of clinical variables were associated with statistical significance to nephropathy in our patients&#58; &#40;a&#41; peripheral neuropathy&#44; angiokeratomas and auditory compromise&#44; clinical manifestations of the classic phenotype &#40;more severe&#41; of FD and &#40;b&#41; structural cardiopathy and CNS involvement&#44; which are major complications&#44; together with nephropathy in affected adult patients&#59; these are responsible for the increased morbidity and mortality and the lower life expectancy&#46; Both types of variables are not early manifestations in patients with FD&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusions</span><p id="par0135" class="elsevierStylePara elsevierViewall">Men with FD present advanced nephropathy at the time of diagnosis&#44; and the nephrologist plays an important role in the diagnosis&#46; There were no diagnoses of index case in pediatric stages&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">As demonstrated in this study&#44; the association of clinical manifestations as variables related with nephropathy could mean the recognition in late stages of kidney damage&#46; It would seem reasonable to continue the search for biomarkers capable of help to make the diagnosis of nephropathy in early stages&#44; which would effectively modify the prognosis of patients affected by this disease&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest related to the content of the submitted work&#46;</p></span></span>"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1128243"
          "palabras" => array:4 [
            0 => "Enfermedad de Fabry"
            1 => "Nefropat&#237;a"
            2 => "Proteinuria"
            3 => "Diagn&#243;stico temprano"
          ]
        ]
      ]
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The early detection of Fabry nephropathy is of interest to us&#46; Its treatment is more effective in early stages&#46; It has been studied by analysing molecular and tissue biomarkers&#46; These have certain disadvantages that hinder its routine use&#46; The aim of this study is to describe the role of the nephrologist in the diagnosis of the disease&#44; and to describe the clinical variables associated with nephropathy in affected patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cross-sectional study&#46; Patients were included from three reference centers in Argentina&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Seventy two patients were studied &#40;26&#46;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;48<span class="elsevierStyleHsp" style=""></span>years&#41;&#58; 30 of which &#40;41&#46;6&#37;&#41; were men and 42 of which &#40;58&#46;4&#37;&#41; were women&#59; 27 pediatric patients and 45 adults&#46; Fourteen &#8220;index cases&#8221; were detected&#44; 50&#37; of which were diagnosed by nephrologists&#46; Nephropathy was found in 44 patients &#40;61&#37;&#41;&#58; 6 pediatric patients and 38 adults&#46; Two types of clinical variables were associated with nephropathy&#58; &#40;i&#41; peripheral nervous system compromise &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; angiokeratomas &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and auditory compromise &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#8211;0&#46;001&#41;&#44; with these being early clinical manifestations of the most severe disease phenotype&#44; and &#40;ii&#41; structural heart disease &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#8211;0&#46;001&#41; and central nervous system compromise &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#8211;0&#46;01&#41;&#44; which are major and late complications&#44; responsible for increased morbidity and mortality and lower life expectancy&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The nephrologist plays an important role in the diagnosis of Fabry nephropathy&#44; although the detection thereof owing to its renal involvement would represent a late diagnosis&#44; because nephropathy is associated with late complications of the most severe disease phenotype&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La detecci&#243;n temprana de la nefropat&#237;a por enfermedad de Fabry es de inter&#233;s&#44; pues su tratamiento es m&#225;s eficaz en estadios precoces&#46; Ha sido estudiada por biomarcadores moleculares y tisulares&#44; pero estos poseen desventajas que dificultan su uso rutinario&#46; El prop&#243;sito del presente trabajo es describir el rol del nefr&#243;logo en el diagn&#243;stico de la enfermedad y las variables cl&#237;nicas asociadas a nefropat&#237;a en pacientes afectados&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio transversal&#46; Se incluyeron pacientes de tres centros de referencia de Argentina&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se estudiaron 72 pacientes &#40;26&#44;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#44;48<span class="elsevierStyleHsp" style=""></span>a&#241;os&#41;&#58; 30 &#40;41&#44;6&#37;&#41; varones y 42 &#40;58&#44;4&#37;&#41; mujeres&#59; 27 pedi&#225;tricos y 45 adultos&#46; Se detectaron 14 &#171;casos &#237;ndice&#187;&#44; el 50&#37; diagnosticados por nefr&#243;logos&#46; Se hall&#243; nefropat&#237;a en 44 pacientes &#40;61&#37;&#41;&#58; 6 pedi&#225;tricos y 38 adultos&#46; Dos tipos de variables cl&#237;nicas se asociaron a nefropat&#237;a&#58; a&#41;<span class="elsevierStyleHsp" style=""></span>compromiso del sistema nervioso perif&#233;rico &#40;p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; angioqueratomas &#40;p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y compromiso auditivo &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01-0&#44;001&#41;&#44; siendo estas manifestaciones cl&#237;nicas tempranas del fenotipo m&#225;s severo de la enfermedad&#44; y b&#41; cardiopat&#237;a estructural &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01-0&#44;001&#41; y compromiso del sistema nervioso central &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05-0&#44;01&#41;&#44; que son complicaciones mayores y tard&#237;as&#44; responsables de la morbimortalidad aumentada y la menor expectativa de vida&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El nefr&#243;logo cumple un rol importante en el diagn&#243;stico de la enfermedad de Fabry&#44; ya que aunque la detecci&#243;n de esta por su compromiso renal significar&#237;a diagn&#243;stico tard&#237;o&#44; debido a que la nefropat&#237;a se asocia a complicaciones tard&#237;as del fenotipo m&#225;s severo de la enfermedad&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
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            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
      ]
    ]
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Jaurretche S&#44; Antongiovanni N&#44; Perretta F&#46; Nefropat&#237;a por enfermedad de Fabry&#46; Rol del nefr&#243;logo y variables cl&#237;nicas asociadas al diagn&#243;stico Nefrologia&#46; 2019&#59;39&#58;294&#8211;300&#46;</p>"
      ]
    ]
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        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 750
            "Ancho" => 1250
            "Tamanyo" => 43818
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Number of &#171;index cases&#187; diagnosed by specialty&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Distribution of nephropathy according to the KDIGO classification&#46; RRT&#58; renal replacement therapy&#46;</p>"
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">HTN&#58; hypertension&#59; CNS&#58; central nervous system&#46;</p>"
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              "tabla" => array:1 [
                0 => """
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Without nephropathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Chi<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Sex&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Male&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;3&#8211;0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Woman&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Age&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Pediatric&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">27&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Activity &#945;-gal-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="left" valign="\n
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                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">21&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="char" valign="\n
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                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#62;0&#46;95&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decreased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Involvement of PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Involvement of GI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&#8211;0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cornea verticilata&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&#8211;0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Angiokeratomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Auditory abnormalities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;01&#8211;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arrhythmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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