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in 1963&#44; the hereditary basis of X-linked AFD was identified&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">9</span></a> However&#44; women can also present AFD with incomplete or intermediate phenotypes&#44; due to the phenomenon of lyonization&#44; which consists of the random activation of the defective X chromosome during mitosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">More than 599 mutations have been identified&#44; the most common of which are produced by a change in the reading pattern&#44; substitution of an amino acid by another or a gene splicing disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a> Most mutations are restricted to specific families&#44; with no clear genotype-phenotype relationship&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Unlike other lysosomal diseases&#44; 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which presumably would be protected by the blood&#8211;brain barrier from increased circulating levels of Gb3&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Secondly&#44; the exclusively cellular distribution of Gb3&#44; especially in the vascular endothelium and smooth muscle&#44; indicate the presence of intracellular production in close relationship with endocytosis or Gb3 dissemination from the circulation to the interior of the cells&#44; where the concentration is 3&#8211;10 times greater than in individuals not affected by AFD&#46; Circulating Gb3 is transported in the low and high-density lipoproteins&#44; at a distribution of 60&#37; and 30&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> The finding that Gb3 deposition is scarce in hepatocytes &#40;in contrast to the accumulation in Kupffer cells&#41; supports the theory that Gb3 synthesized in the hepatocytes is associated with lipoproteins and is secreted with the lipoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">19</span></a> This complex&#44; released into circulation&#44; binds to the vascular endothelial membrane and smooth muscle cells&#44; which have high-affinity receptors for lipoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> This mechanism would also be involved to a lesser degree with dissemination or fluid-phase &#40;nonadsorptive&#41; endocytosis of globosides or plasma Gb3&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Due to the fact that lysosomes in all cells are deficient in AGA activity&#44; the accumulated glycosphingolipids in the form of multivesicular bodies or in more advanced stages as free intracytoplasmic masses can lead to cellular dysfunction or degeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a> Lastly&#44; we know that glycosphingolipids are also synthesized in bone marrow&#44; where they are transformed and incorporated into the membranes of the formed elements of blood&#46; Globosides &#40;complex lipids of the glycosphingolipid family&#41; of the membrane of the aged erythrocytes are thereby released into circulation and catabolized in the spleen&#44; producing Gb3&#46; As a result&#44; erythrocyte turnover and that of other senescent blood cells contribute to the increase in glycosphingolipids&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">20</span></a> The total quantity of accumulated glycosphingolipids in a given tissue is therefore dependent on the time&#44; the accumulation rate of the intracellular and circulatory types&#44; the possibility of excretion and the presence or absence of residual AGA activity&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Vascular structural disorders</span><p id="par0045" class="elsevierStylePara elsevierViewall">AFD produces vascular wall disorders that involve the formation of microaneurysms in the retinal vessels and conjunctiva&#44; as well as telangiectasia and angiokeratoma&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">21</span></a> Vasomotor activity control is also affected&#44; due to the vascular lesion and the Gb3 deposits in the autonomic ganglia and myelin sheaths&#46; There is an initial restriction for vasoconstriction and&#44; in more advanced phases&#44; for vasodilation&#44; which explains the patients&#8217; intolerance to temperature fluctuations&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Activated endothelium</span><p id="par0050" class="elsevierStylePara elsevierViewall">This term is defined by the expression and release of proinflammatory molecules by endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Recent studies have shown that exposure of circulating leukocytes and endothelial cells to low-density lipoproteins and glycosphingolipids increases the expression of the adhesion molecules of leukocytes and integrin Mac-1 &#40;a ligand of a leukocyte adhesion molecule&#41;&#46; This process results in increased interaction between the leukocytes and the endothelium&#44; which promotes the activation&#44; production and release of other proinflammatory molecules such as interleukin 1 beta &#40;IL-1&#946;&#41; and tumor necrosis factor alpha &#40;TNF-&#945;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">23</span></a> The increased interaction between leukocytes and the endothelium is partly responsible for the activation of the endothelium&#44; through adhesion of these cells by molecules such as integrin Mac-1&#46; Furthermore&#44; the VCAM-1 molecule intervenes in the adhesion to the endothelial wall&#44; thus determining the activation of the nicotinamide adenine dinucleotide phosphate &#40;NADPH&#41;-oxidase in the membrane of the endothelial cells&#46; VCAM-1 also activates the matrix metalloproteinases&#44; which&#44; in turn&#44; degrade the extracellular matrix&#44; allowing for the migration of endothelial cells&#44; a phenomenon known as &#8220;endothelial activation&#8221;&#44; and increases capillary patency&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">22&#44;24&#8211;26</span></a> Regardless of the above&#44; NADPH-oxidase activation induces the synthesis of reactive oxygen species &#40;ROS&#41;&#44; which perpetuates the interaction of the lymphocytes with the endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">It has also been confirmed that the expression of superoxide dismutase 2 &#40;SOD2&#41;&#44; a mitochondrial antioxidant&#44; is reduced in patients with AFD&#46; In this respect&#44; excess accumulation of Gb3 suppresses SOD2 synthesis&#44; which causes an increase in ROS and&#44; in turn&#44; an activation of cAMP-dependent protein kinases &#40;AMPK&#41;&#44; causing mitochondrial damage that results in endothelial dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">27</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Furthermore&#44; the nitric oxide &#40;NO&#41; pathway has been implicated in the activation and endothelial dysfunction of AFD&#46; Classically&#44; it has been postulated that circulating Gb3 is deposited in the intima and media layers of the arteries&#44; promoting the proliferation of smooth muscle cells&#46; This proliferation facilitates the production of angiotensin&#44; with the consequent production of ROS and reduction of NO synthesis by endothelial NO synthase &#40;eNOS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> An alternative hypothesis proposes that Gb3 deposition produces reduced eNOS activity&#44; with lower NO production and an increase in ROS&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> When vascular damage is caused by ROS&#44; an increase has been observed in the risk of carotid thrombosis&#44; which is correlated with age and Gb3 deposition&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">29</span></a> Gb3 overload has also been associated with increased transcription of the intercellular adhesion molecule 1 &#40;ICAM-1&#41;&#44; VCAM-1 and E-selectin&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> Just as ROS play a fundamental role in the protection of the vascular endothelium in vascular diseases&#44; the hyperpolarized factors of the endothelium simultaneously protect the endothelial cells of the lesion&#44; through a mechanism that depends on the calcium-activated potassium channels &#40;K<span class="elsevierStyleInf">Ca</span>&#41; 3&#46;1 and 2&#46;3&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">30&#44;31</span></a> It has been shown that accumulated Gb3 causes K<span class="elsevierStyleInf">Ca</span> 3&#46;1 channel degradation&#44; through a clathrin-dependent process&#44; which leads to lower vasodilation&#46; Furthermore&#44; it has been documented that recovery of these channels leads to normalization of endothelial dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">30&#8211;32</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prothrombotic state</span><p id="par0065" class="elsevierStylePara elsevierViewall">The activation of IL-1&#946;&#44; TNF&#945; and other molecules in patients with AFD promotes a prothrombotic state&#44; increasing the risk of ischemic events&#46; It has been observed that levels of various adhesion molecules are high in these patients and that the expression of integrin MAC-1 in monocytes is increased&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> Increased levels of ICAM-1 and Mac-1 in patients with AFD are also indicative of an increase in the interaction between the endothelium and inflammatory cells&#44; which explains the early vascular invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> An increase in plasminogen activator inhibitor levels has also been confirmed&#44; as well as a reduction in thrombomodulin&#44; which favors the thrombolytic action of the endothelium and the procoagulant state in this disease in early stages of life&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> The prevalence of stroke in patients with AFD is 10&#8211;15&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">33&#44;34</span></a> Primary prevention of cardiac and cerebrovascular events&#44; suppression of modifiable risk factors&#44; prevention of potential drug interactions&#44; the early initiation of enzyme replacement therapy &#40;ERT&#41;&#44; when indicated&#44; and even the use of angiotensin-converting enzyme inhibitors and antiplatelet agents is therefore especially important for patients with AFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">35&#44;36</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pathophysiology of cardiac involvement</span><p id="par0070" class="elsevierStylePara elsevierViewall">In patients with AFD&#44; coronary flow reserve is severely reduced&#46; These findings correspond to the extensive remodeling of the intramural arterioles&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Glycosphingolipid deposition in the endothelium has been classically considered the cause of the vascular abnormalities in AFD&#59; however&#44; there is no directly proportional relationship between vascular damage and the amount of Gb3 deposition&#46; It has therefore been proposed that other mechanisms could be involved&#46; It is believed that the primary enzymatic defect produces a cascade of events that causes endothelial dysfunction and impaired arterial remodeling&#44; causing occlusive phenomena and thrombosis of small and medium arteries with the corresponding infarction in the medium and long term&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">37&#8211;39</span></a> In AFD&#44; not only are the arteries changed due to endothelial damage but there is also accelerated hypertrophy in the medium-caliber arteries&#44; with increased intima-media thickness&#44; affecting the distensibility of the arteries&#44; due to hypertrophy of the smooth muscle cells&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">24</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Gb3 deposition&#44; microcirculation ischemia and impaired expression of adhesion molecules in myocardial cells promotes inflammation&#44; increased extracellular matrix deposition and fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> It has been postulated that myocardial cell and excito-conduction tissue dysfunction in AFD is produced by impaired NO production&#46; The constitutive isoforms eNOS and neural NOS &#40;nNOS&#41; produce small quantities of NO&#44; which acts as a regulator of vasodilation&#46; Due to the reduced NO&#44; endothelial dysfunction is produced&#44; which ends up damaging the myofilaments and DNA&#44; which promotes cell apoptosis and leads to electrical instability and conduction disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">40</span></a> In contrast&#44; inducible NOS &#40;iNOS&#41; allows cells to release large quantities of NO in response to inflammatory cytokines&#46; The cytotoxic activity of NO by itself is weak but can react with ROS&#44; generating nitrotyrosine&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> which causes structural impairment of the myofilaments and protein kinases&#44; altering contractility and distensibility through phosphorylation of these enzymes&#46; The oxidative damage in the DNA of cardiomyocytes has been described in several conditions&#44; such as myocardial ischemia&#44; cardiomyopathies and heart failure&#44; causing mutagenic effects and cell death&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> Thus&#44; apoptosis was shown to be 187-fold greater in patients with AFD than in control patients&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> It has been observed in women with AFD that immunohistochemical detection of iNOS and nitrotyrosine is limited to affected areas of the heart&#44; which indicates the direct effect of Gb3 and its metabolites&#44; inducing intracellular oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Pathophysiology of renal impairment</span><p id="par0080" class="elsevierStylePara elsevierViewall">Renal impairment in AFD is mainly characterized by early damage to podocytes and fibrosis produced in epithelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">26&#44;42</span></a> Podocytes cover and participate in the patency of the glomerular basement membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">43</span></a> Damage to podocytes can be observed in the absence of proteinuria in patients with AFD during childhood and adolescence&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;44&#8211;46</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Our knowledge of the pathogenesis of glomerulosclerosis in AFD is limited&#46; In podocytes&#44; Gb3 deposition increases the expression of the fibrogenic cytokine TGF-&#946;1&#44; which increases extracellular matrix synthesis &#40;fibronectin and type IV collagen&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> Gb3 promotes an inflammatory condition similar to that of hyperglycemia&#46; Gb3 promotes the release of inflammatory cytokines through the CD74 receptor pathway&#44; thereby modulating the function of podocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;47</span></a> The damage to podocytes is the event that triggers chronic kidney disease with proteinuria&#44; and the loss of podocytes leads to glomerulosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> Most recently&#44; podocytes have been recognized as the cells that are loaded with glycolipids the soonest&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> The loss of podocytes is observed at this point in children with minimal albuminuria and therefore plays a fundamental role in the progression of nephropathy in AFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;45</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition to the direct effects of glycolipids in tubular cells&#44; proteinuria by itself could activate tubular cells and induce an inflammatory response and interstitial fibrosis&#46; It has been shown that the family of Akt proteins &#40;serine&#47;threonine kinases&#41; inhibits the podocyte apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">48</span></a> The loss of Akt2 or the reduction of one of its phosphorylations can worsen the podocyte lesion&#44; promoting the onset of proteinuria&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">48</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">AGA-deficient podocytes show pronounced alteration of protein LC3-II&#44; which is a marker of autophagy that is produced in basal form and after Akt induction&#46; The amount of LC3-II is correlated with the number of autophagosomes&#44; which suggests that podocyte autophagy is activated in patients with AFD&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> Mammalian target of rapamycin &#40;mTOR&#41; signaling has been identified as a critical regulator of autophagy&#44; suppressing the formation of autophagic vesicles&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> Recent data have also implicated the mTOR signaling of podocytes in the regulation of autophagosomes and the regeneration of autolysosome vesicles&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> In patients with AFD&#44; an impairment in podocyte regulation can directly affect the stability of Akt and mTOR and autophagy signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a> Similarly&#44; after Atk induction through IL-1&#946; signaling&#44; the podocytes show reduced activity of the Akt-mTOR pathway&#44; which reinforces the theory that autophagy is increased in the podocytes of patients with Fabry disease&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Gb3 can activate the innate immunity-related&#44; Toll-like receptor type 4 &#40;TLR4&#41;-dependent and cluster of differentiation 1d &#40;CD1d&#41; pathways&#44; promoting inflammatory cascades through invariant natural killer T cells &#40;iNKTs&#41;&#46; TLR4 can also increase TGF-&#946; expression in podocytes&#44; leading to extracellular matrix remodeling and glomerular fibrosis&#44; which also contributes to the nephropathy of AFD&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">From a structural viewpoint&#44; the first renal event that occurs in AFD is pedicel effacement&#44; even in the absence of proteinuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;51</span></a> A renal biopsy would therefore serve as a marker of early impairment&#44; with important implications in terms of the indication for ERT&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pathophysiology of nervous system involvement</span><p id="par0110" class="elsevierStylePara elsevierViewall">The pathophysiological basis of neuronal damage is not well known&#46; It has been proposed that the peripheral nervous system accumulates Gb3 in both the Schwann cells and in the dorsal spinal lymph nodes&#44; affecting the small fibers A-delta and C&#44; resulting not only in neuropathic pain but also autonomic abnormalities&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">52&#44;53</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">With regard to central nervous system involvement&#44; the presence of &#8220;cerebral angiopathy&#8221; has been postulated&#44; in which the intimately involved elements are endothelial dysfunction&#44; brain hyperperfusion and a ROS-dependent prothrombotic state&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Biomarkers in Fabry disease</span><p id="par0120" class="elsevierStylePara elsevierViewall">There is no ideal biomarker in AFD&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">55</span></a> Proteinuria and albuminuria can be useful in assessing nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">55</span></a> Cystatin C and the amino-terminal fragment of the brain natriuretic propeptide &#40;NT-proBNP&#41; are useful as biomarkers of early renal damage in patients with AFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">56&#44;57</span></a> The usefulness of NT-proBNP as a diagnostic and prognostic predictor of heart disease has subsequently been confirmed&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">58&#8211;60</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Measuring Gb3 concentrations in plasma and especially in urine is diagnostic for most patients&#46; However&#44; the values can be normal in a number of variants of the disease or in certain GLA gene mutations&#46; Globotriaosylsphingosine &#40;Lyso-Gb3&#41;&#44; a Gb3 derivative&#44; can also have prognostic utility for hemizygous women and for monitoring the response to ERT&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">61&#44;62</span></a> Lyso-Gb3 levels are higher in the plasma of male patients and in patients with a classical phenotype compared with hemizygous patients&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> In women&#44; both symptomatic and asymptomatic&#44; plasma Lyso-Gb3 levels are high proportionally to the reduced activity of AGA&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> However&#44; there is no correlation between urinary lyso-Gb3 levels and glomerular filtration rate and cannot therefore be considered a single marker of renal impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">64</span></a> Lyso-Gb3 levels in urine and plasma have been shown to decrease in patients after a year of ERT&#44; which is associated in women with reduced left ventricular hypertrophy and<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">65</span></a> in both sexes with a reduced risk of developing new lesions in the white matter of the central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">65</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Other potential biomarkers in AFD are plasma 3-nitrotyrosine&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> podocyturia and urinary excretion of CD80&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">64</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary&#44; the pathophysiology of AFD encompasses numerous molecular abnormalities that involve damage to the endothelial and muscle cells of the vessels&#44; cardiomyocytes and cardiac excito-conduction system&#44; as well as renal podocyte dysfunction &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Our understanding of the pathophysiology of the nervous system impairment is highly limited&#46; There is a need for studies to help identify new therapeutic targets and reliable biomarkers for diagnosis and prognosis&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">Dr&#46; Torralba is a consultant of <span class="elsevierStyleGrantSponsor" id="gs1">Genzyme Corporation</span> and <span class="elsevierStyleGrantSponsor" id="gs2">Shire Company</span> and has participated as speaker in conferences on lysosomal storage diseases&#46; Dr&#46; Torralba has received financial support for research studies of both companies&#46; This article&#44; however&#44; was prepared independently in its entirety&#46;</p></span></span>"
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          "titulo" => "Background"
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          "identificador" => "sec0010"
          "titulo" => "Vascular dysfunction"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Globotriaosylceramide deposition"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Vascular structural disorders"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Activated endothelium"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Prothrombotic state"
            ]
          ]
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        6 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Pathophysiology of cardiac involvement"
        ]
        7 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Pathophysiology of renal impairment"
        ]
        8 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Pathophysiology of nervous system involvement"
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        9 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Biomarkers in Fabry disease"
        ]
        10 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflicts of interest"
        ]
        11 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2016-12-07"
    "fechaAceptado" => "2017-06-12"
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            0 => "Fabry disease"
            1 => "Pathophysiology"
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          "titulo" => "Palabras clave"
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          "palabras" => array:2 [
            0 => "Enfermedad de Fabry"
            1 => "Fisiopatolog&#237;a"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Fabry disease is a lysosomal condition with systemic clinical expression&#44; caused by the tissue deposit of globotriaosylceramide&#44; due to a deficit in its degradation&#46; As with most lysosomal diseases&#44; the presence of a mutation in a gene does not explain the pathophysiological disorders shown by patients&#46; We conducted a comprehensive review of the pathogenic mechanisms that occur in Fabry disease&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de Fabry es una entidad lisosomal de expresi&#243;n cl&#237;nica sist&#233;mica&#44; causada por el dep&#243;sito tisular de globotriaosilceramida&#44; debido a un d&#233;ficit en su degradaci&#243;n&#46; Como en la mayor&#237;a de las enfermedades lisosomales&#44; la existencia de una mutaci&#243;n en un gen no explica las alteraciones fisiopatol&#243;gicas que presentan los pacientes&#46; Se realiza una revisi&#243;n exhaustiva de los mecanismos patog&#233;nicos que acontecen en la enfermedad de Fabry&#46;</p></span>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:65 [
            0 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "2002 &#91;updated 2017&#93;"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Mehta"
                            1 => "D&#46; Hughes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:2 [
                        "titulo" => "GeneReviews<span class="elsevierStyleSup">&#174;</span> &#40;Internet&#41;"
                        "serieFecha" => "1993&#8211;2017"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry&#39;s disease&#58; alpha-galactosidase deficiency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;A&#46; Kint"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "1970"
                        "volumen" => "167"
                        "paginaInicial" => "1268"
                        "paginaFinal" => "1269"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5411915"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The enzyme defect in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;A&#46; Kint"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1970"
                        "volumen" => "227"
                        "paginaInicial" => "1173"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5451124"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of lysosomal storage disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "P&#46;J&#46; Meikle"
                            1 => "J&#46;J&#46; Hopwood"
                            2 => "A&#46;E&#46; Clague"
                            3 => "W&#46;F&#46; Carey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1999"
                        "volumen" => "281"
                        "paginaInicial" => "249"
                        "paginaFinal" => "254"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9918480"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The frequency of lysosomal storage diseases in The Netherlands"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;J&#46; Poorthuis"
                            1 => "R&#46;A&#46; Wevers"
                            2 => "W&#46;J&#46; Kleijer"
                            3 => "J&#46;E&#46; Groener"
                            4 => "J&#46;G&#46; de Jong"
                            5 => "S&#46; van Weely"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Hum Gen"
                        "fecha" => "1999"
                        "volumen" => "105"
                        "paginaInicial" => "151"
                        "paginaFinal" => "156"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High incidence of later-onset Fabry disease revealed by newborn screening"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Spada"
                            1 => "S&#46; Pagliardini"
                            2 => "M&#46; Yasuda"
                            3 => "T&#46; Tukel"
                            4 => "G&#46; Thiagarajan"
                            5 => "H&#46; Sakuraba"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/504601"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Hum Genet"
                        "fecha" => "2006"
                        "volumen" => "79"
                        "paginaInicial" => "31"
                        "paginaFinal" => "40"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16773563"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A case of angioqueratoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "W&#46; Anderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "1898"
                        "volumen" => "10"
                        "paginaInicial" => "113"
                        "paginaFinal" => "117"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ein beitrag zur kenntonis der purpura haemorrhagica nodularis &#40;purpura papulosa haemorrhagica Hebrae&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; Fabry"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol Syph"
                        "fecha" => "1898"
                        "volumen" => "43"
                        "paginaInicial" => "187"
                        "paginaFinal" => "200"
                        "itemHostRev" => array:3 [
                          "pii" => "S0264410X15011196"
                          "estado" => "S300"
                          "issn" => "0264410X"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Angiokeratoma corporis diffusum&#46; A clinical study of eight affected families"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46; Wise"
                            1 => "H&#46;J&#46; Wallace"
                            2 => "E&#46;H&#46; Jellinek"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Q J Med"
                        "fecha" => "1962"
                        "volumen" => "31"
                        "paginaInicial" => "177"
                        "paginaFinal" => "206"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14007664"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The molecular defect leading to Fabry disease&#58; structure of human alpha-galactosidase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;C&#46; Garman"
                            1 => "D&#46;N&#46; Garbozci"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jmb.2004.01.035"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Mol Biol"
                        "fecha" => "2004"
                        "volumen" => "337"
                        "paginaInicial" => "319"
                        "paginaFinal" => "335"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15003450"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0264410X15003084"
                          "estado" => "S300"
                          "issn" => "0264410X"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "X-chromosome inactivation and human genetic disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;F&#46; Lyon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Paediatr Suppl"
                        "fecha" => "2002"
                        "volumen" => "439"
                        "paginaInicial" => "107"
                        "paginaFinal" => "112"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease&#44; an underrecognized multisystemic disorder&#58; expert recommendations for diagnosis&#44; management&#44; and enzyme replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;J&#46; Desnick"
                            1 => "R&#46; Brady"
                            2 => "J&#46; Barranger"
                            3 => "A&#46;J&#46; Collins"
                            4 => "D&#46;P&#46; Germain"
                            5 => "M&#46; Glodman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ann Inter Med"
                        "fecha" => "2003"
                        "volumen" => "138"
                        "paginaInicial" => "338"
                        "paginaFinal" => "346"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Alpha galactosidase A deficiency&#58; Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46;J&#46; Desnick"
                            1 => "Y&#46;A&#46; Ioannou"
                            2 => "C&#46;M&#46; Eng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "The metabolic and molecular base of inheritance disease"
                        "paginaInicial" => "3733"
                        "paginaFinal" => "3774"
                        "edicion" => "8th ed&#46;"
                        "serieFecha" => "2001"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of Fabry disease in patients with cryptogenic stroke&#58; a prospective study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Rolfs"
                            1 => "T&#46; Bottcher"
                            2 => "M&#46; Zschiesche"
                            3 => "P&#46; Morris"
                            4 => "B&#46; Winchester"
                            5 => "P&#46; Bauer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(05)67635-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2005"
                        "volumen" => "366"
                        "paginaInicial" => "1794"
                        "paginaFinal" => "1796"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16298216"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vascular cell adhesion molecule 1 &#40;VCAM-1&#41; activation of endothelial cell matrix metalloproteinases&#58; role of reactive oxygen species"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46;L&#46; Deem"
                            1 => "J&#46;M&#46; Cook-Mills"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2004-02-0665"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2004"
                        "volumen" => "104"
                        "paginaInicial" => "2385"
                        "paginaFinal" => "2393"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15265790"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Elevated globotriaosylsphingosine is a hallmark of Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Aerts"
                            1 => "J&#46;E&#46; Groener"
                            2 => "S&#46; Kuiper"
                            3 => "W&#46;E&#46; Donker-Koopman"
                            4 => "A&#46; Strijland"
                            5 => "R&#46; Ottenhoff"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.0712309105"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci U S A"
                        "fecha" => "2008"
                        "volumen" => "105"
                        "paginaInicial" => "2812"
                        "paginaFinal" => "2817"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18287059"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry&#39;s disease on the mechanism of the peripheral nerve involvement"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "N&#46; Fukuhara"
                            1 => "M&#46; Suzuki"
                            2 => "N&#46; Fujita"
                            3 => "T&#46; Tsubaki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Neuropathol"
                        "fecha" => "1975"
                        "volumen" => "33"
                        "paginaInicial" => "9"
                        "paginaFinal" => "21"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/809981"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Disfunci&#243;n endotelial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Badim&#243;n"
                            1 => "J&#46; Mart&#237;nez-Gonz&#225;lez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Esp Cardiol"
                        "fecha" => "2006"
                        "volumen" => "6"
                        "paginaInicial" => "21"
                        "paginaFinal" => "30"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ultrastructural and biochemical liver analyses in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;G&#46; Meuwissen"
                            1 => "K&#46;P&#46; Dingemans"
                            2 => "A&#46; Strijland"
                            3 => "J&#46;M&#46; Tager"
                            4 => "B&#46;C&#46; Ooms"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1982"
                        "volumen" => "2"
                        "paginaInicial" => "263"
                        "paginaFinal" => "268"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6802742"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            19 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neutral glycosphingolipids of serum lipoproteins in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;T&#46; Clarke"
                            1 => "J&#46;M&#46; Stoltz"
                            2 => "M&#46;R&#46; Mulcahey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "1976"
                        "volumen" => "431"
                        "paginaInicial" => "317"
                        "paginaFinal" => "325"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/181056"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ocular manifestations of Fabry&#39;s disease&#58; data from the Fabry outcome survey"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Sodi"
                            1 => "A&#46;S&#46; Ioannidis"
                            2 => "A&#46; Mehta"
                            3 => "C&#46; Davey"
                            4 => "M&#46; Beck"
                            5 => "S&#46; Pitz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bjo.2006.100602"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Ophthalmol"
                        "fecha" => "2007"
                        "volumen" => "91"
                        "paginaInicial" => "210"
                        "paginaFinal" => "214"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16973664"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Coronary microvascular dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46;G&#46; Camici"
                            1 => "F&#46; Crea"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra061889"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2007"
                        "volumen" => "356"
                        "paginaInicial" => "830"
                        "paginaFinal" => "840"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17314342"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Innate and adaptive immune response in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46; Mauhin"
                            1 => "O&#46; Lidove"
                            2 => "E&#46; Masat"
                            3 => "F&#46; Mingozzi"
                            4 => "K&#46; Mariampillai"
                            5 => "J&#46;M&#46; Ziza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/8904_2014_371"
                      "Revista" => array:6 [
                        "tituloSerie" => "JIMD Rep"
                        "fecha" => "2015"
                        "volumen" => "22"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25690728"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Arterial remodelling in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "P&#46; Boutouyrie"
                            1 => "S&#46; Laurent"
                            2 => "B&#46; Laloux"
                            3 => "O&#46; Lidove"
                            4 => "J&#46;P&#46; Grunfeld"
                            5 => "D&#46;P&#46; Germain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Paediatr Suppl"
                        "fecha" => "2002"
                        "volumen" => "91"
                        "paginaInicial" => "62"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12572845"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0450"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Progressive podocyte injury and globotriaosylceramide &#40;GL-3&#41; accumulation in young patients with Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Najafian"
                            1 => "E&#46; Svarstad"
                            2 => "L&#46; Bostad"
                            3 => "M&#46;C&#46; Gubler"
                            4 => "C&#46; T&#248;ndel"
                            5 => "C&#46; Whitley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ki.2010.484"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2011"
                        "volumen" => "79"
                        "paginaInicial" => "663"
                        "paginaFinal" => "670"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21160462"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0455"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vascular cell adhesion molecule-1 expression and signaling during disease&#58; regulation by reactive oxygen species and antioxidants"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;M&#46; Cook-Mills"
                            1 => "M&#46;E&#46; Marchese"
                            2 => "H&#46; Abdala-Valencia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/ars.2010.3522"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antioxid Redox Signal"
                        "fecha" => "2011"
                        "volumen" => "15"
                        "paginaInicial" => "1607"
                        "paginaFinal" => "1638"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21050132"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0460"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Imbalanced production of reactive oxygen species and mitochondrial antioxidant-SOD2 in Fabry disease-specific human induced pluripotent stem cell-differentiated vascular endotelial cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46; Tseng"
                            1 => "S&#46; Chou"
                            2 => "H&#46; Chiang"
                            3 => "M&#46; Wang"
                            4 => "C&#46; Chien"
                            5 => "K&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3727/096368916X694265"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Transplant"
                        "fecha" => "2017"
                        "volumen" => "26"
                        "paginaInicial" => "513"
                        "paginaFinal" => "527"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27938475"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Shu"
                            1 => "A&#46; Vivekanandan-Giri"
                            2 => "S&#46; Pennathur"
                            3 => "B&#46;E&#46; Smid"
                            4 => "J&#46;M&#46; Aerts"
                            5 => "C&#46;E&#46; Hollak"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ki.2013.520"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2014"
                        "volumen" => "86"
                        "paginaInicial" => "58"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24402087"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0470"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease in mice is associated with age-dependent susceptibility to vascular trombosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;T&#46; Eitzman"
                            1 => "P&#46;F&#46; Bodary"
                            2 => "Y&#46; Shen"
                            3 => "C&#46;G&#46; Khairallah"
                            4 => "S&#46;R&#46; Wild"
                            5 => "A&#46; Abe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Soc Nephrol"
                        "fecha" => "2003"
                        "volumen" => "14"
                        "paginaInicial" => "298"
                        "paginaFinal" => "302"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12538729"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0475"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylceramide induces lysosomal degradation of endothelial KCa3&#46;1 in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Choi"
                            1 => "J&#46;A&#46; Kim"
                            2 => "H&#46;Y&#46; Na"
                            3 => "S&#46;E&#46; Cho"
                            4 => "S&#46; Park"
                            5 => "S&#46;C&#46; Jung"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/ATVBAHA.113.302200"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arterioscler Thromb Vasc Biol"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "81"
                        "paginaFinal" => "89"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24158513"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0480"
              "etiqueta" => "31"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylceramide leads to K&#40;Ca&#41;3&#46;1 channel dysfunction&#58; a new insight into endothelial dysfunction in Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            2 => "K&#46;Y&#46; Joo"
                            3 => "S&#46; Choi"
                            4 => "E&#46;N&#46; Choi"
                            5 => "J&#46;A&#46; Shin"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cvr/cvq333"
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                        "tituloSerie" => "Cardiovasc Res"
                        "fecha" => "2011"
                        "volumen" => "89"
                        "paginaInicial" => "290"
                        "paginaFinal" => "299"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20971723"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0485"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylceramide induces endothelial dysfunction in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "K&#46; Satoh"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/ATVBAHA.113.302744"
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                        "tituloSerie" => "Arterioscler Thromb Vasc Biol"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "2"
                        "paginaFinal" => "4"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24335674"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            32 => array:3 [
              "identificador" => "bib0490"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of Fabry disease in young patients with cryptogenic ischemic stroke"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "V&#46; Dubuc"
                            1 => "D&#46;F&#46; Moore"
                            2 => "L&#46;C&#46; Gioia"
                            3 => "G&#46; Saposnik"
                            4 => "D&#46; Selchen"
                            5 => "S&#46; Lanthier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jstrokecerebrovasdis.2012.10.005"
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                        "tituloSerie" => "J Stroke Cerebrovasc Dis"
                        "fecha" => "2013"
                        "volumen" => "22"
                        "paginaInicial" => "1288"
                        "paginaFinal" => "1292"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23168217"
                            "web" => "Medline"
                          ]
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                      ]
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                ]
              ]
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              "identificador" => "bib0495"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Natural history of the cerebrovascular complications of Fabry disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Mehta"
                            1 => "L&#46; Ginsberg"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Pediatr Suppl"
                        "fecha" => "2005"
                        "volumen" => "94"
                        "paginaInicial" => "24"
                        "paginaFinal" => "27"
                      ]
                    ]
                  ]
                ]
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              "identificador" => "bib0500"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease and factor V Leiden&#58; a potent vascular risk combination"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Tchan"
                            1 => "D&#46; Sillence"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1445-5994.2011.02483.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intern Med J"
                        "fecha" => "2011"
                        "volumen" => "41"
                        "paginaInicial" => "422"
                        "paginaFinal" => "426"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21605293"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            35 => array:3 [
              "identificador" => "bib0505"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thromboembolic events in Fabry disease and the impact of factor V Leiden"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Lenders"
                            1 => "N&#46; Karabul"
                            2 => "T&#46; Duning"
                            3 => "B&#46; Schmitz"
                            4 => "M&#46; Schelleckes"
                            5 => "R&#46; Mesters"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1212/WNL.0000000000001333"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurology"
                        "fecha" => "2015"
                        "volumen" => "84"
                        "paginaInicial" => "1009"
                        "paginaFinal" => "1016"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25663229"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            36 => array:3 [
              "identificador" => "bib0510"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Profile of endothelial and leukocyte activation in Fabry patients"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; DeGraba"
                            1 => "S&#46; Azhar"
                            2 => "F&#46; Dignat-George"
                            3 => "E&#46; Brown"
                            4 => "B&#46; Bouti&#232;re"
                            5 => "G&#46; Altarescu"
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Neurol"
                        "fecha" => "2000"
                        "volumen" => "47"
                        "paginaInicial" => "229"
                        "paginaFinal" => "233"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10665494"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            37 => array:3 [
              "identificador" => "bib0515"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "White matter lesion severity in male and female patients with Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Fellgiebel"
                            1 => "M&#46;J&#46; Muller"
                            2 => "M&#46; Mazanek"
                            3 => "K&#46; Baron"
                            4 => "M&#46; Beck"
                            5 => "P&#46; Stoeter"
                          ]
                        ]
                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1212/01.wnl.0000173030.70057.eb"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurology"
                        "fecha" => "2005"
                        "volumen" => "65"
                        "paginaInicial" => "600"
                        "paginaFinal" => "602"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16116124"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0520"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease and the heart"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "N&#46; Seydelmann"
                            1 => "C&#46; Wanner"
                            2 => "S&#46; St&#246;rk"
                            3 => "G&#46; Ertl"
                            4 => "F&#46; Weidemann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.beem.2014.10.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Best Pract Res Clin Endocrinol Metab"
                        "fecha" => "2015"
                        "volumen" => "29"
                        "paginaInicial" => "195"
                        "paginaFinal" => "204"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25987173"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0525"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Electrocardiographic changes and arrhythmia in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46; Namdar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fcvm.2016.00007"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Cardiovasc Med"
                        "fecha" => "2016"
                        "volumen" => "3"
                        "paginaInicial" => "7"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27047943"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0530"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased oxidative stress contributes to cardiomyocyte dysfunction and death in patients with Fabry disease cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Chimenti"
                            1 => "F&#46; Scopelliti"
                            2 => "E&#46; Vulpis"
                            3 => "M&#46; Tafani"
                            4 => "L&#46; Villanova"
                            5 => "R&#46; Verardo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.humpath.2015.07.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Pathol"
                        "fecha" => "2015"
                        "volumen" => "46"
                        "paginaInicial" => "1760"
                        "paginaFinal" => "1768"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26362204"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibrosis&#58; a key feature of Fabry disease with potential therapeutic implications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Weidemann"
                            1 => "M&#46;D&#46; S&#225;nchez-Ni&#241;o"
                            2 => "J&#46; Politei"
                            3 => "J&#46;P&#46; Oliveira"
                            4 => "C&#46; Wanner"
                            5 => "D&#46;G&#46; Warnock"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1750-1172-8-116"
                      "Revista" => array:5 [
                        "tituloSerie" => "Orphanet J Rare Dis"
                        "fecha" => "2013"
                        "volumen" => "8"
                        "paginaInicial" => "116"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23915644"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "When foots come first&#58; early signs of podocyte injury in Fabry nephropathy without proteinuria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "F&#46; Becherucci"
                            1 => "P&#46; Romagnani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000369307"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nephron"
                        "fecha" => "2015"
                        "volumen" => "129"
                        "paginaInicial" => "3"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25592473"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; T&#248;ndel"
                            1 => "T&#46; Kanai"
                            2 => "K&#46;K&#46; Larsen"
                            3 => "S&#46; Ito"
                            4 => "J&#46;M&#46; Politei"
                            5 => "D&#46;G&#46; Warnock"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000369309"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nephron"
                        "fecha" => "2015"
                        "volumen" => "129"
                        "paginaInicial" => "16"
                        "paginaFinal" => "21"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25531941"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "C&#46; T&#248;ndel"
                            1 => "L&#46; Bostad"
                            2 => "A&#46; Hirth"
                            3 => "E&#46; Svarstad"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.ajkd.2007.12.032"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Kidney Dis"
                        "fecha" => "2008"
                        "volumen" => "51"
                        "paginaInicial" => "767"
                        "paginaFinal" => "776"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18436087"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Podocyte pathology and nephropathy &#8211; sphingolipids in glomerular diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Merscher"
                            1 => "A&#46; Fornoni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Front Endocrinol &#40;Lausanne&#41;"
                        "fecha" => "2014"
                        "volumen" => "5"
                        "paginaInicial" => "127"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylsphingosine actions on human glomerular podocytes&#58; implications for Fabry nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;D&#46; S&#225;nchez-Ni&#241;o"
                            1 => "A&#46;B&#46; Sanz"
                            2 => "S&#46; Carrasco"
                            3 => "M&#46;A&#46; Saleem"
                            4 => "P&#46;W&#46; Mathieson"
                            5 => "J&#46;M&#46; Valdivieso"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfq306"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nephrol Dial Transplant"
                        "fecha" => "2011"
                        "volumen" => "26"
                        "paginaInicial" => "1797"
                        "paginaFinal" => "1802"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20504837"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibici&#243;n de mTOR&#44; prote&#237;nas Akt y enfermedad renal cr&#243;nica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46; M&#225;rquez"
                            1 => "J&#46; Pascual"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3265/Nefrologia.pre2014.Apr.12381"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nefrolog&#237;a"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "425"
                        "paginaFinal" => "427"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25036055"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dysregulated autophagy contributes to podocyte damage in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;C&#46; Liebau"
                            1 => "F&#46; Braun"
                            2 => "K&#46; H&#246;pker"
                            3 => "C&#46; Weitbrecht"
                            4 => "V&#46; Bartels"
                            5 => "R&#46;U&#46; M&#252;ller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2013"
                        "volumen" => "8"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Possible role of transforming growth factor-&#946;1 and vascular endothelial growth factor in Fabry disease nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;H&#46; Lee"
                            1 => "E&#46;N&#46; Choi"
                            2 => "Y&#46;J&#46; Jeon"
                            3 => "S&#46;C&#46; Jung"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/ijmm.2012.1139"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Mol Med"
                        "fecha" => "2012"
                        "volumen" => "30"
                        "paginaInicial" => "1275"
                        "paginaFinal" => "1280"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23007467"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease&#58; the European Fabry Working Group consensus document"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Biegstraaten"
                            1 => "R&#46; Arngr&#237;msson"
                            2 => "F&#46; Barbey"
                            3 => "L&#46; Boks"
                            4 => "F&#46; Cecchi"
                            5 => "P&#46;B&#46; Deegan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13023-015-0253-6"
                      "Revista" => array:5 [
                        "tituloSerie" => "Orphanet J Rare Dis"
                        "fecha" => "2015"
                        "volumen" => "10"
                        "paginaInicial" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25885911"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neuropathy and Fabry disease&#58; pathogenesis and enzyme replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Schiffmann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Neurol Belg"
                        "fecha" => "2006"
                        "volumen" => "106"
                        "paginaInicial" => "61"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16898255"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Choi"
                            1 => "J&#46; Vernon"
                            2 => "O&#46; Kopach"
                            3 => "M&#46;S&#46; Minett"
                            4 => "K&#46; Milks"
                            5 => "P&#46;T&#46; Clayton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.neulet.2015.01.084"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurosci Lett"
                        "fecha" => "2015"
                        "volumen" => "594"
                        "paginaInicial" => "163"
                        "paginaFinal" => "168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25697597"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The cerebral vasculopathy of Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46;F&#46; Moore"
                            1 => "C&#46;R&#46; Kaneski"
                            2 => "H&#46; Askari"
                            3 => "R&#46; Schiffmann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jns.2007.01.053"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurol Sci"
                        "fecha" => "2007"
                        "volumen" => "257"
                        "paginaInicial" => "258"
                        "paginaFinal" => "263"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17362993"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry nephropaty&#58; a review &#8211; how can we optimize the management of Fabry nephropaty"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Waldek"
                            1 => "S&#46; Feriozzi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2369-15-72"
                      "Revista" => array:6 [
                        "tituloSerie" => "BMC Nephrol"
                        "fecha" => "2014"
                        "volumen" => "15"
                        "paginaInicial" => "72"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24886109"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NT-proBNP as prognostic biomarkers in Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Torralba-Cabeza"
                            1 => "S&#46; Olivera"
                            2 => "D&#46;A&#46; Hughes"
                            3 => "G&#46;M&#46; Pastores"
                            4 => "R&#46;N&#46; Mateo"
                            5 => "J&#46;I&#46; P&#233;rez-Calvo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                  "contribucion" => array:1 [
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                        "paginaInicial" => "105"
                        "paginaFinal" => "111"
                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
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              ]
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            59 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with Anderson&#8211;Fabry disease"
                      "autores" => array:1 [
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                          "autores" => array:6 [
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                            1 => "V&#46; Parisi"
                            2 => "M&#46; Ramos"
                            3 => "K&#46; Janagarajan"
                            4 => "C&#46; O&#8217;Mahony"
                            5 => "A&#46; Dawnay"
                          ]
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                      ]
                    ]
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                        "fecha" => "2013"
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                        "paginaInicial" => "111"
                        "paginaFinal" => "117"
                        "link" => array:1 [
                          0 => array:2 [
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                      ]
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                ]
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                    0 => array:2 [
                      "titulo" => "Enfermedad de Fabry"
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                      ]
                    ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                            4 => "M&#46;C&#46; Glubler"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25386848"
                            "web" => "Medline"
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                    ]
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                ]
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            62 => array:3 [
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                    0 => array:2 [
                      "titulo" => "Plasma globotriaosylsphingosine as a biomarker of Fabry disease"
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "T&#46; Kodama"
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                            3 => "K&#46; Sugawara"
                            4 => "T&#46; Tsukimura"
                            5 => "T&#46; Ohashi"
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                  "host" => array:1 [
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                        "paginaFinal" => "261"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20409739"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0645"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                    0 => array:2 [
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26337460"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Vascular aspects of Fabry disease in relation to clinical manifestations and elevations in plasma globotriaosylsphingosine"
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Review
The pathophysiology of Fabry disease
Fisiopatología de la enfermedad de Fabry
S. Olivera-Gonzáleza,
Corresponding author
susana.olivera@yahoo.es

Corresponding author.
, C. Josa-Laordenb, M.A. Torralba-Cabezaa
a Unidad de Enfermedades Minoritarias, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
b Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Degradation pathway for complex lipids&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anderson&#8211;Fabry disease &#40;AFD&#41; is an inherited condition caused by lysosomal dysfunction linked to chromosome X and caused by mutations in the GLA gene located in chromosome Xq22&#46;1 and which encodes the alpha-galactosidase A &#40;AGA&#41; enzyme&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a> Complete or partial deficiency of this enzyme alters the degradation of glycosphingolipids from cell membranes&#44; producing the intracellular accumulation of globotriaosylceramide &#40;Gb3&#41; and other lipid complexes in the kidneys&#44; nervous system and heart &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">2&#44;3</span></a> AFD is the second most common lysosomal storage disease after Gaucher&#39;s disease&#46; Its annual incidence is estimated at 1&#47;40&#44;000&#8211;1&#47;117&#44;000 living male newborns<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">4</span></a> but is probably underestimated due to undiagnosed cases&#46; In Spain&#44; a rate of 1&#47;400&#44;000 males has been reported&#44; significantly lower than that of other Mediterranean countries such as Italy&#44; France and Portugal&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">5</span></a> If the clinical variants of AFD with late onset or mild impairment are considered&#44; the prevalence could be as high as 1&#47;3000 individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1&#44;6</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Fabry and Anderson simultaneously reported the first patients with angiokeratoma and renal impairment with albuminuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">7&#44;8</span></a> Subsequently&#44; in 1963&#44; the hereditary basis of X-linked AFD was identified&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">9</span></a> However&#44; women can also present AFD with incomplete or intermediate phenotypes&#44; due to the phenomenon of lyonization&#44; which consists of the random activation of the defective X chromosome during mitosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">More than 599 mutations have been identified&#44; the most common of which are produced by a change in the reading pattern&#44; substitution of an amino acid by another or a gene splicing disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">12</span></a> Most mutations are restricted to specific families&#44; with no clear genotype-phenotype relationship&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Unlike other lysosomal diseases&#44; Gb3 accumulates in all cells of the body&#44; although mainly in the vascular endothelium and&#44; to a lesser extent&#44; in the neurons&#44; myocytes and the heart&#39;s excito-conduction system&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a> The most common manifestations in childhood and adolescence are neuropathic pain&#44; hypohidrosis&#47;anhidrosis&#44; angiokeratoma&#44; cornea verticillata and microalbuminuria&#46; Subsequently&#44; renal impairment progresses and heart disease and cerebrovascular disease appear&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Vascular dysfunction</span><p id="par0025" class="elsevierStylePara elsevierViewall">Vascular dysfunction is the main pathophysiological disorder of AFD&#44; in whose pathogenesis the following factors participate&#58; &#40;1&#41; Gb3 accumulation&#44; &#40;2&#41; structural abnormalities in the vessel walls&#44; &#40;3&#41; activated endothelium and &#40;4&#41; the presence of a prothrombotic state&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">14&#44;15</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Globotriaosylceramide deposition</span><p id="par0030" class="elsevierStylePara elsevierViewall">The origin of the Gb3 accumulation has not been sufficiently established&#46; Firstly&#44; this deposit has been shown to come from endogenous synthesis and the subsequent lysosomal accumulation of the terminal &#945;-galactosyl portion contained in the glycosphingolipids&#44; as well as from autophagocytosis of the cell membranes that contain these lipid complexes&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">16</span></a> This mechanism is the most important for accumulation in avascular sites such as the cornea and neurons&#44; which presumably would be protected by the blood&#8211;brain barrier from increased circulating levels of Gb3&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Secondly&#44; the exclusively cellular distribution of Gb3&#44; especially in the vascular endothelium and smooth muscle&#44; indicate the presence of intracellular production in close relationship with endocytosis or Gb3 dissemination from the circulation to the interior of the cells&#44; where the concentration is 3&#8211;10 times greater than in individuals not affected by AFD&#46; Circulating Gb3 is transported in the low and high-density lipoproteins&#44; at a distribution of 60&#37; and 30&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> The finding that Gb3 deposition is scarce in hepatocytes &#40;in contrast to the accumulation in Kupffer cells&#41; supports the theory that Gb3 synthesized in the hepatocytes is associated with lipoproteins and is secreted with the lipoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">19</span></a> This complex&#44; released into circulation&#44; binds to the vascular endothelial membrane and smooth muscle cells&#44; which have high-affinity receptors for lipoproteins&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> This mechanism would also be involved to a lesser degree with dissemination or fluid-phase &#40;nonadsorptive&#41; endocytosis of globosides or plasma Gb3&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Due to the fact that lysosomes in all cells are deficient in AGA activity&#44; the accumulated glycosphingolipids in the form of multivesicular bodies or in more advanced stages as free intracytoplasmic masses can lead to cellular dysfunction or degeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a> Lastly&#44; we know that glycosphingolipids are also synthesized in bone marrow&#44; where they are transformed and incorporated into the membranes of the formed elements of blood&#46; Globosides &#40;complex lipids of the glycosphingolipid family&#41; of the membrane of the aged erythrocytes are thereby released into circulation and catabolized in the spleen&#44; producing Gb3&#46; As a result&#44; erythrocyte turnover and that of other senescent blood cells contribute to the increase in glycosphingolipids&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">20</span></a> The total quantity of accumulated glycosphingolipids in a given tissue is therefore dependent on the time&#44; the accumulation rate of the intracellular and circulatory types&#44; the possibility of excretion and the presence or absence of residual AGA activity&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Vascular structural disorders</span><p id="par0045" class="elsevierStylePara elsevierViewall">AFD produces vascular wall disorders that involve the formation of microaneurysms in the retinal vessels and conjunctiva&#44; as well as telangiectasia and angiokeratoma&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">21</span></a> Vasomotor activity control is also affected&#44; due to the vascular lesion and the Gb3 deposits in the autonomic ganglia and myelin sheaths&#46; There is an initial restriction for vasoconstriction and&#44; in more advanced phases&#44; for vasodilation&#44; which explains the patients&#8217; intolerance to temperature fluctuations&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Activated endothelium</span><p id="par0050" class="elsevierStylePara elsevierViewall">This term is defined by the expression and release of proinflammatory molecules by endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Recent studies have shown that exposure of circulating leukocytes and endothelial cells to low-density lipoproteins and glycosphingolipids increases the expression of the adhesion molecules of leukocytes and integrin Mac-1 &#40;a ligand of a leukocyte adhesion molecule&#41;&#46; This process results in increased interaction between the leukocytes and the endothelium&#44; which promotes the activation&#44; production and release of other proinflammatory molecules such as interleukin 1 beta &#40;IL-1&#946;&#41; and tumor necrosis factor alpha &#40;TNF-&#945;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">23</span></a> The increased interaction between leukocytes and the endothelium is partly responsible for the activation of the endothelium&#44; through adhesion of these cells by molecules such as integrin Mac-1&#46; Furthermore&#44; the VCAM-1 molecule intervenes in the adhesion to the endothelial wall&#44; thus determining the activation of the nicotinamide adenine dinucleotide phosphate &#40;NADPH&#41;-oxidase in the membrane of the endothelial cells&#46; VCAM-1 also activates the matrix metalloproteinases&#44; which&#44; in turn&#44; degrade the extracellular matrix&#44; allowing for the migration of endothelial cells&#44; a phenomenon known as &#8220;endothelial activation&#8221;&#44; and increases capillary patency&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">22&#44;24&#8211;26</span></a> Regardless of the above&#44; NADPH-oxidase activation induces the synthesis of reactive oxygen species &#40;ROS&#41;&#44; which perpetuates the interaction of the lymphocytes with the endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">It has also been confirmed that the expression of superoxide dismutase 2 &#40;SOD2&#41;&#44; a mitochondrial antioxidant&#44; is reduced in patients with AFD&#46; In this respect&#44; excess accumulation of Gb3 suppresses SOD2 synthesis&#44; which causes an increase in ROS and&#44; in turn&#44; an activation of cAMP-dependent protein kinases &#40;AMPK&#41;&#44; causing mitochondrial damage that results in endothelial dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">27</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Furthermore&#44; the nitric oxide &#40;NO&#41; pathway has been implicated in the activation and endothelial dysfunction of AFD&#46; Classically&#44; it has been postulated that circulating Gb3 is deposited in the intima and media layers of the arteries&#44; promoting the proliferation of smooth muscle cells&#46; This proliferation facilitates the production of angiotensin&#44; with the consequent production of ROS and reduction of NO synthesis by endothelial NO synthase &#40;eNOS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> An alternative hypothesis proposes that Gb3 deposition produces reduced eNOS activity&#44; with lower NO production and an increase in ROS&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> When vascular damage is caused by ROS&#44; an increase has been observed in the risk of carotid thrombosis&#44; which is correlated with age and Gb3 deposition&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">29</span></a> Gb3 overload has also been associated with increased transcription of the intercellular adhesion molecule 1 &#40;ICAM-1&#41;&#44; VCAM-1 and E-selectin&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> Just as ROS play a fundamental role in the protection of the vascular endothelium in vascular diseases&#44; the hyperpolarized factors of the endothelium simultaneously protect the endothelial cells of the lesion&#44; through a mechanism that depends on the calcium-activated potassium channels &#40;K<span class="elsevierStyleInf">Ca</span>&#41; 3&#46;1 and 2&#46;3&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">30&#44;31</span></a> It has been shown that accumulated Gb3 causes K<span class="elsevierStyleInf">Ca</span> 3&#46;1 channel degradation&#44; through a clathrin-dependent process&#44; which leads to lower vasodilation&#46; Furthermore&#44; it has been documented that recovery of these channels leads to normalization of endothelial dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">30&#8211;32</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prothrombotic state</span><p id="par0065" class="elsevierStylePara elsevierViewall">The activation of IL-1&#946;&#44; TNF&#945; and other molecules in patients with AFD promotes a prothrombotic state&#44; increasing the risk of ischemic events&#46; It has been observed that levels of various adhesion molecules are high in these patients and that the expression of integrin MAC-1 in monocytes is increased&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> Increased levels of ICAM-1 and Mac-1 in patients with AFD are also indicative of an increase in the interaction between the endothelium and inflammatory cells&#44; which explains the early vascular invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> An increase in plasminogen activator inhibitor levels has also been confirmed&#44; as well as a reduction in thrombomodulin&#44; which favors the thrombolytic action of the endothelium and the procoagulant state in this disease in early stages of life&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">15</span></a> The prevalence of stroke in patients with AFD is 10&#8211;15&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">33&#44;34</span></a> Primary prevention of cardiac and cerebrovascular events&#44; suppression of modifiable risk factors&#44; prevention of potential drug interactions&#44; the early initiation of enzyme replacement therapy &#40;ERT&#41;&#44; when indicated&#44; and even the use of angiotensin-converting enzyme inhibitors and antiplatelet agents is therefore especially important for patients with AFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">35&#44;36</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pathophysiology of cardiac involvement</span><p id="par0070" class="elsevierStylePara elsevierViewall">In patients with AFD&#44; coronary flow reserve is severely reduced&#46; These findings correspond to the extensive remodeling of the intramural arterioles&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Glycosphingolipid deposition in the endothelium has been classically considered the cause of the vascular abnormalities in AFD&#59; however&#44; there is no directly proportional relationship between vascular damage and the amount of Gb3 deposition&#46; It has therefore been proposed that other mechanisms could be involved&#46; It is believed that the primary enzymatic defect produces a cascade of events that causes endothelial dysfunction and impaired arterial remodeling&#44; causing occlusive phenomena and thrombosis of small and medium arteries with the corresponding infarction in the medium and long term&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">37&#8211;39</span></a> In AFD&#44; not only are the arteries changed due to endothelial damage but there is also accelerated hypertrophy in the medium-caliber arteries&#44; with increased intima-media thickness&#44; affecting the distensibility of the arteries&#44; due to hypertrophy of the smooth muscle cells&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">24</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Gb3 deposition&#44; microcirculation ischemia and impaired expression of adhesion molecules in myocardial cells promotes inflammation&#44; increased extracellular matrix deposition and fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> It has been postulated that myocardial cell and excito-conduction tissue dysfunction in AFD is produced by impaired NO production&#46; The constitutive isoforms eNOS and neural NOS &#40;nNOS&#41; produce small quantities of NO&#44; which acts as a regulator of vasodilation&#46; Due to the reduced NO&#44; endothelial dysfunction is produced&#44; which ends up damaging the myofilaments and DNA&#44; which promotes cell apoptosis and leads to electrical instability and conduction disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">40</span></a> In contrast&#44; inducible NOS &#40;iNOS&#41; allows cells to release large quantities of NO in response to inflammatory cytokines&#46; The cytotoxic activity of NO by itself is weak but can react with ROS&#44; generating nitrotyrosine&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> which causes structural impairment of the myofilaments and protein kinases&#44; altering contractility and distensibility through phosphorylation of these enzymes&#46; The oxidative damage in the DNA of cardiomyocytes has been described in several conditions&#44; such as myocardial ischemia&#44; cardiomyopathies and heart failure&#44; causing mutagenic effects and cell death&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> Thus&#44; apoptosis was shown to be 187-fold greater in patients with AFD than in control patients&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> It has been observed in women with AFD that immunohistochemical detection of iNOS and nitrotyrosine is limited to affected areas of the heart&#44; which indicates the direct effect of Gb3 and its metabolites&#44; inducing intracellular oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Pathophysiology of renal impairment</span><p id="par0080" class="elsevierStylePara elsevierViewall">Renal impairment in AFD is mainly characterized by early damage to podocytes and fibrosis produced in epithelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">26&#44;42</span></a> Podocytes cover and participate in the patency of the glomerular basement membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">43</span></a> Damage to podocytes can be observed in the absence of proteinuria in patients with AFD during childhood and adolescence&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;44&#8211;46</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Our knowledge of the pathogenesis of glomerulosclerosis in AFD is limited&#46; In podocytes&#44; Gb3 deposition increases the expression of the fibrogenic cytokine TGF-&#946;1&#44; which increases extracellular matrix synthesis &#40;fibronectin and type IV collagen&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> Gb3 promotes an inflammatory condition similar to that of hyperglycemia&#46; Gb3 promotes the release of inflammatory cytokines through the CD74 receptor pathway&#44; thereby modulating the function of podocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;47</span></a> The damage to podocytes is the event that triggers chronic kidney disease with proteinuria&#44; and the loss of podocytes leads to glomerulosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> Most recently&#44; podocytes have been recognized as the cells that are loaded with glycolipids the soonest&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> The loss of podocytes is observed at this point in children with minimal albuminuria and therefore plays a fundamental role in the progression of nephropathy in AFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;45</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition to the direct effects of glycolipids in tubular cells&#44; proteinuria by itself could activate tubular cells and induce an inflammatory response and interstitial fibrosis&#46; It has been shown that the family of Akt proteins &#40;serine&#47;threonine kinases&#41; inhibits the podocyte apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">48</span></a> The loss of Akt2 or the reduction of one of its phosphorylations can worsen the podocyte lesion&#44; promoting the onset of proteinuria&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">48</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">AGA-deficient podocytes show pronounced alteration of protein LC3-II&#44; which is a marker of autophagy that is produced in basal form and after Akt induction&#46; The amount of LC3-II is correlated with the number of autophagosomes&#44; which suggests that podocyte autophagy is activated in patients with AFD&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> Mammalian target of rapamycin &#40;mTOR&#41; signaling has been identified as a critical regulator of autophagy&#44; suppressing the formation of autophagic vesicles&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> Recent data have also implicated the mTOR signaling of podocytes in the regulation of autophagosomes and the regeneration of autolysosome vesicles&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">49</span></a> In patients with AFD&#44; an impairment in podocyte regulation can directly affect the stability of Akt and mTOR and autophagy signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a> Similarly&#44; after Atk induction through IL-1&#946; signaling&#44; the podocytes show reduced activity of the Akt-mTOR pathway&#44; which reinforces the theory that autophagy is increased in the podocytes of patients with Fabry disease&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Gb3 can activate the innate immunity-related&#44; Toll-like receptor type 4 &#40;TLR4&#41;-dependent and cluster of differentiation 1d &#40;CD1d&#41; pathways&#44; promoting inflammatory cascades through invariant natural killer T cells &#40;iNKTs&#41;&#46; TLR4 can also increase TGF-&#946; expression in podocytes&#44; leading to extracellular matrix remodeling and glomerular fibrosis&#44; which also contributes to the nephropathy of AFD&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">From a structural viewpoint&#44; the first renal event that occurs in AFD is pedicel effacement&#44; even in the absence of proteinuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">42&#44;51</span></a> A renal biopsy would therefore serve as a marker of early impairment&#44; with important implications in terms of the indication for ERT&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pathophysiology of nervous system involvement</span><p id="par0110" class="elsevierStylePara elsevierViewall">The pathophysiological basis of neuronal damage is not well known&#46; It has been proposed that the peripheral nervous system accumulates Gb3 in both the Schwann cells and in the dorsal spinal lymph nodes&#44; affecting the small fibers A-delta and C&#44; resulting not only in neuropathic pain but also autonomic abnormalities&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">52&#44;53</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">With regard to central nervous system involvement&#44; the presence of &#8220;cerebral angiopathy&#8221; has been postulated&#44; in which the intimately involved elements are endothelial dysfunction&#44; brain hyperperfusion and a ROS-dependent prothrombotic state&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Biomarkers in Fabry disease</span><p id="par0120" class="elsevierStylePara elsevierViewall">There is no ideal biomarker in AFD&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">55</span></a> Proteinuria and albuminuria can be useful in assessing nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">55</span></a> Cystatin C and the amino-terminal fragment of the brain natriuretic propeptide &#40;NT-proBNP&#41; are useful as biomarkers of early renal damage in patients with AFD&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">56&#44;57</span></a> The usefulness of NT-proBNP as a diagnostic and prognostic predictor of heart disease has subsequently been confirmed&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">58&#8211;60</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Measuring Gb3 concentrations in plasma and especially in urine is diagnostic for most patients&#46; However&#44; the values can be normal in a number of variants of the disease or in certain GLA gene mutations&#46; Globotriaosylsphingosine &#40;Lyso-Gb3&#41;&#44; a Gb3 derivative&#44; can also have prognostic utility for hemizygous women and for monitoring the response to ERT&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">61&#44;62</span></a> Lyso-Gb3 levels are higher in the plasma of male patients and in patients with a classical phenotype compared with hemizygous patients&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> In women&#44; both symptomatic and asymptomatic&#44; plasma Lyso-Gb3 levels are high proportionally to the reduced activity of AGA&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> However&#44; there is no correlation between urinary lyso-Gb3 levels and glomerular filtration rate and cannot therefore be considered a single marker of renal impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">64</span></a> Lyso-Gb3 levels in urine and plasma have been shown to decrease in patients after a year of ERT&#44; which is associated in women with reduced left ventricular hypertrophy and<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">65</span></a> in both sexes with a reduced risk of developing new lesions in the white matter of the central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">65</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Other potential biomarkers in AFD are plasma 3-nitrotyrosine&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">28</span></a> podocyturia and urinary excretion of CD80&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">64</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary&#44; the pathophysiology of AFD encompasses numerous molecular abnormalities that involve damage to the endothelial and muscle cells of the vessels&#44; cardiomyocytes and cardiac excito-conduction system&#44; as well as renal podocyte dysfunction &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Our understanding of the pathophysiology of the nervous system impairment is highly limited&#46; There is a need for studies to help identify new therapeutic targets and reliable biomarkers for diagnosis and prognosis&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">Dr&#46; Torralba is a consultant of <span class="elsevierStyleGrantSponsor" id="gs1">Genzyme Corporation</span> and <span class="elsevierStyleGrantSponsor" id="gs2">Shire Company</span> and has participated as speaker in conferences on lysosomal storage diseases&#46; Dr&#46; Torralba has received financial support for research studies of both companies&#46; This article&#44; however&#44; was prepared independently in its entirety&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Fabry disease is a lysosomal condition with systemic clinical expression&#44; caused by the tissue deposit of globotriaosylceramide&#44; due to a deficit in its degradation&#46; As with most lysosomal diseases&#44; the presence of a mutation in a gene does not explain the pathophysiological disorders shown by patients&#46; We conducted a comprehensive review of the pathogenic mechanisms that occur in Fabry disease&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de Fabry es una entidad lisosomal de expresi&#243;n cl&#237;nica sist&#233;mica&#44; causada por el dep&#243;sito tisular de globotriaosilceramida&#44; debido a un d&#233;ficit en su degradaci&#243;n&#46; Como en la mayor&#237;a de las enfermedades lisosomales&#44; la existencia de una mutaci&#243;n en un gen no explica las alteraciones fisiopatol&#243;gicas que presentan los pacientes&#46; Se realiza una revisi&#243;n exhaustiva de los mecanismos patog&#233;nicos que acontecen en la enfermedad de Fabry&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Olivera-Gonz&#225;lez S&#44; Josa-Laorden C&#44; Torralba-Cabeza MA&#46; Fisiopatolog&#237;a de la enfermedad de Fabry&#46; Rev Clin Esp&#46; 2018&#59;218&#58;22&#8211;28&#46;</p>"
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            0 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "2002 &#91;updated 2017&#93;"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Mehta"
                            1 => "D&#46; Hughes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:2 [
                        "titulo" => "GeneReviews<span class="elsevierStyleSup">&#174;</span> &#40;Internet&#41;"
                        "serieFecha" => "1993&#8211;2017"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry&#39;s disease&#58; alpha-galactosidase deficiency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;A&#46; Kint"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "1970"
                        "volumen" => "167"
                        "paginaInicial" => "1268"
                        "paginaFinal" => "1269"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5411915"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The enzyme defect in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;A&#46; Kint"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1970"
                        "volumen" => "227"
                        "paginaInicial" => "1173"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5451124"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of lysosomal storage disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "P&#46;J&#46; Meikle"
                            1 => "J&#46;J&#46; Hopwood"
                            2 => "A&#46;E&#46; Clague"
                            3 => "W&#46;F&#46; Carey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1999"
                        "volumen" => "281"
                        "paginaInicial" => "249"
                        "paginaFinal" => "254"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9918480"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The frequency of lysosomal storage diseases in The Netherlands"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;J&#46; Poorthuis"
                            1 => "R&#46;A&#46; Wevers"
                            2 => "W&#46;J&#46; Kleijer"
                            3 => "J&#46;E&#46; Groener"
                            4 => "J&#46;G&#46; de Jong"
                            5 => "S&#46; van Weely"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Hum Gen"
                        "fecha" => "1999"
                        "volumen" => "105"
                        "paginaInicial" => "151"
                        "paginaFinal" => "156"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High incidence of later-onset Fabry disease revealed by newborn screening"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Spada"
                            1 => "S&#46; Pagliardini"
                            2 => "M&#46; Yasuda"
                            3 => "T&#46; Tukel"
                            4 => "G&#46; Thiagarajan"
                            5 => "H&#46; Sakuraba"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/504601"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Hum Genet"
                        "fecha" => "2006"
                        "volumen" => "79"
                        "paginaInicial" => "31"
                        "paginaFinal" => "40"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16773563"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A case of angioqueratoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "W&#46; Anderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Br J Dermatol"
                        "fecha" => "1898"
                        "volumen" => "10"
                        "paginaInicial" => "113"
                        "paginaFinal" => "117"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ein beitrag zur kenntonis der purpura haemorrhagica nodularis &#40;purpura papulosa haemorrhagica Hebrae&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; Fabry"
                          ]
                        ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol Syph"
                        "fecha" => "1898"
                        "volumen" => "43"
                        "paginaInicial" => "187"
                        "paginaFinal" => "200"
                        "itemHostRev" => array:3 [
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                0 => array:2 [
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                      "titulo" => "Angiokeratoma corporis diffusum&#46; A clinical study of eight affected families"
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                          "autores" => array:3 [
                            0 => "D&#46; Wise"
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                            2 => "E&#46;H&#46; Jellinek"
                          ]
                        ]
                      ]
                    ]
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                      "Revista" => array:6 [
                        "tituloSerie" => "Q J Med"
                        "fecha" => "1962"
                        "volumen" => "31"
                        "paginaInicial" => "177"
                        "paginaFinal" => "206"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14007664"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "The molecular defect leading to Fabry disease&#58; structure of human alpha-galactosidase"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;C&#46; Garman"
                            1 => "D&#46;N&#46; Garbozci"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.jmb.2004.01.035"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Mol Biol"
                        "fecha" => "2004"
                        "volumen" => "337"
                        "paginaInicial" => "319"
                        "paginaFinal" => "335"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15003450"
                            "web" => "Medline"
                          ]
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                          "pii" => "S0264410X15003084"
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                          "issn" => "0264410X"
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              "identificador" => "bib0380"
              "etiqueta" => "11"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "X-chromosome inactivation and human genetic disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;F&#46; Lyon"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Paediatr Suppl"
                        "fecha" => "2002"
                        "volumen" => "439"
                        "paginaInicial" => "107"
                        "paginaFinal" => "112"
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0385"
              "etiqueta" => "12"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease&#44; an underrecognized multisystemic disorder&#58; expert recommendations for diagnosis&#44; management&#44; and enzyme replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;J&#46; Desnick"
                            1 => "R&#46; Brady"
                            2 => "J&#46; Barranger"
                            3 => "A&#46;J&#46; Collins"
                            4 => "D&#46;P&#46; Germain"
                            5 => "M&#46; Glodman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ann Inter Med"
                        "fecha" => "2003"
                        "volumen" => "138"
                        "paginaInicial" => "338"
                        "paginaFinal" => "346"
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0390"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Alpha galactosidase A deficiency&#58; Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46;J&#46; Desnick"
                            1 => "Y&#46;A&#46; Ioannou"
                            2 => "C&#46;M&#46; Eng"
                          ]
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                      ]
                    ]
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                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "The metabolic and molecular base of inheritance disease"
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                        "paginaFinal" => "3774"
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                        "serieFecha" => "2001"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Prevalence of Fabry disease in patients with cryptogenic stroke&#58; a prospective study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Rolfs"
                            1 => "T&#46; Bottcher"
                            2 => "M&#46; Zschiesche"
                            3 => "P&#46; Morris"
                            4 => "B&#46; Winchester"
                            5 => "P&#46; Bauer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(05)67635-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2005"
                        "volumen" => "366"
                        "paginaInicial" => "1794"
                        "paginaFinal" => "1796"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16298216"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0400"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vascular cell adhesion molecule 1 &#40;VCAM-1&#41; activation of endothelial cell matrix metalloproteinases&#58; role of reactive oxygen species"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46;L&#46; Deem"
                            1 => "J&#46;M&#46; Cook-Mills"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2004-02-0665"
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                        "tituloSerie" => "Blood"
                        "fecha" => "2004"
                        "volumen" => "104"
                        "paginaInicial" => "2385"
                        "paginaFinal" => "2393"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15265790"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Elevated globotriaosylsphingosine is a hallmark of Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Aerts"
                            1 => "J&#46;E&#46; Groener"
                            2 => "S&#46; Kuiper"
                            3 => "W&#46;E&#46; Donker-Koopman"
                            4 => "A&#46; Strijland"
                            5 => "R&#46; Ottenhoff"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1073/pnas.0712309105"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci U S A"
                        "fecha" => "2008"
                        "volumen" => "105"
                        "paginaInicial" => "2812"
                        "paginaFinal" => "2817"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18287059"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry&#39;s disease on the mechanism of the peripheral nerve involvement"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "N&#46; Fukuhara"
                            1 => "M&#46; Suzuki"
                            2 => "N&#46; Fujita"
                            3 => "T&#46; Tsubaki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Neuropathol"
                        "fecha" => "1975"
                        "volumen" => "33"
                        "paginaInicial" => "9"
                        "paginaFinal" => "21"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/809981"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Disfunci&#243;n endotelial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Badim&#243;n"
                            1 => "J&#46; Mart&#237;nez-Gonz&#225;lez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Esp Cardiol"
                        "fecha" => "2006"
                        "volumen" => "6"
                        "paginaInicial" => "21"
                        "paginaFinal" => "30"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ultrastructural and biochemical liver analyses in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;G&#46; Meuwissen"
                            1 => "K&#46;P&#46; Dingemans"
                            2 => "A&#46; Strijland"
                            3 => "J&#46;M&#46; Tager"
                            4 => "B&#46;C&#46; Ooms"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1982"
                        "volumen" => "2"
                        "paginaInicial" => "263"
                        "paginaFinal" => "268"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6802742"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neutral glycosphingolipids of serum lipoproteins in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;T&#46; Clarke"
                            1 => "J&#46;M&#46; Stoltz"
                            2 => "M&#46;R&#46; Mulcahey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "1976"
                        "volumen" => "431"
                        "paginaInicial" => "317"
                        "paginaFinal" => "325"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/181056"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ocular manifestations of Fabry&#39;s disease&#58; data from the Fabry outcome survey"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Sodi"
                            1 => "A&#46;S&#46; Ioannidis"
                            2 => "A&#46; Mehta"
                            3 => "C&#46; Davey"
                            4 => "M&#46; Beck"
                            5 => "S&#46; Pitz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bjo.2006.100602"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Ophthalmol"
                        "fecha" => "2007"
                        "volumen" => "91"
                        "paginaInicial" => "210"
                        "paginaFinal" => "214"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16973664"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Coronary microvascular dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46;G&#46; Camici"
                            1 => "F&#46; Crea"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra061889"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2007"
                        "volumen" => "356"
                        "paginaInicial" => "830"
                        "paginaFinal" => "840"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17314342"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0440"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Innate and adaptive immune response in Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            2 => "E&#46; Masat"
                            3 => "F&#46; Mingozzi"
                            4 => "K&#46; Mariampillai"
                            5 => "J&#46;M&#46; Ziza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/8904_2014_371"
                      "Revista" => array:6 [
                        "tituloSerie" => "JIMD Rep"
                        "fecha" => "2015"
                        "volumen" => "22"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25690728"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Arterial remodelling in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "P&#46; Boutouyrie"
                            1 => "S&#46; Laurent"
                            2 => "B&#46; Laloux"
                            3 => "O&#46; Lidove"
                            4 => "J&#46;P&#46; Grunfeld"
                            5 => "D&#46;P&#46; Germain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Paediatr Suppl"
                        "fecha" => "2002"
                        "volumen" => "91"
                        "paginaInicial" => "62"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12572845"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0450"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Progressive podocyte injury and globotriaosylceramide &#40;GL-3&#41; accumulation in young patients with Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            2 => "L&#46; Bostad"
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                            4 => "C&#46; T&#248;ndel"
                            5 => "C&#46; Whitley"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ki.2010.484"
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                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2011"
                        "volumen" => "79"
                        "paginaInicial" => "663"
                        "paginaFinal" => "670"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21160462"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0455"
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              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Vascular cell adhesion molecule-1 expression and signaling during disease&#58; regulation by reactive oxygen species and antioxidants"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            2 => "H&#46; Abdala-Valencia"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/ars.2010.3522"
                      "Revista" => array:6 [
                        "tituloSerie" => "Antioxid Redox Signal"
                        "fecha" => "2011"
                        "volumen" => "15"
                        "paginaInicial" => "1607"
                        "paginaFinal" => "1638"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21050132"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
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              "identificador" => "bib0460"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Imbalanced production of reactive oxygen species and mitochondrial antioxidant-SOD2 in Fabry disease-specific human induced pluripotent stem cell-differentiated vascular endotelial cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46; Tseng"
                            1 => "S&#46; Chou"
                            2 => "H&#46; Chiang"
                            3 => "M&#46; Wang"
                            4 => "C&#46; Chien"
                            5 => "K&#46; Chen"
                          ]
                        ]
                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3727/096368916X694265"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Transplant"
                        "fecha" => "2017"
                        "volumen" => "26"
                        "paginaInicial" => "513"
                        "paginaFinal" => "527"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27938475"
                            "web" => "Medline"
                          ]
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                ]
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              "identificador" => "bib0465"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Shu"
                            1 => "A&#46; Vivekanandan-Giri"
                            2 => "S&#46; Pennathur"
                            3 => "B&#46;E&#46; Smid"
                            4 => "J&#46;M&#46; Aerts"
                            5 => "C&#46;E&#46; Hollak"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ki.2013.520"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2014"
                        "volumen" => "86"
                        "paginaInicial" => "58"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24402087"
                            "web" => "Medline"
                          ]
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                ]
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              "identificador" => "bib0470"
              "etiqueta" => "29"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease in mice is associated with age-dependent susceptibility to vascular trombosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;T&#46; Eitzman"
                            1 => "P&#46;F&#46; Bodary"
                            2 => "Y&#46; Shen"
                            3 => "C&#46;G&#46; Khairallah"
                            4 => "S&#46;R&#46; Wild"
                            5 => "A&#46; Abe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Soc Nephrol"
                        "fecha" => "2003"
                        "volumen" => "14"
                        "paginaInicial" => "298"
                        "paginaFinal" => "302"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12538729"
                            "web" => "Medline"
                          ]
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                      ]
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                ]
              ]
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              "identificador" => "bib0475"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylceramide induces lysosomal degradation of endothelial KCa3&#46;1 in Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Choi"
                            1 => "J&#46;A&#46; Kim"
                            2 => "H&#46;Y&#46; Na"
                            3 => "S&#46;E&#46; Cho"
                            4 => "S&#46; Park"
                            5 => "S&#46;C&#46; Jung"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
                        "tituloSerie" => "Arterioscler Thromb Vasc Biol"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "81"
                        "paginaFinal" => "89"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24158513"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
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              "identificador" => "bib0480"
              "etiqueta" => "31"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Globotriaosylceramide leads to K&#40;Ca&#41;3&#46;1 channel dysfunction&#58; a new insight into endothelial dysfunction in Fabry disease"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Park"
                            1 => "J&#46;A&#46; Kim"
                            2 => "K&#46;Y&#46; Joo"
                            3 => "S&#46; Choi"
                            4 => "E&#46;N&#46; Choi"
                            5 => "J&#46;A&#46; Shin"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cvr/cvq333"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cardiovasc Res"
                        "fecha" => "2011"
                        "volumen" => "89"
                        "paginaInicial" => "290"
                        "paginaFinal" => "299"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20971723"
                            "web" => "Medline"
                          ]
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                ]
              ]
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            31 => array:3 [
              "identificador" => "bib0485"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylceramide induces endothelial dysfunction in Fabry disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "K&#46; Satoh"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/ATVBAHA.113.302744"
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                        "tituloSerie" => "Arterioscler Thromb Vasc Biol"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "2"
                        "paginaFinal" => "4"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24335674"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
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              "identificador" => "bib0490"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of Fabry disease in young patients with cryptogenic ischemic stroke"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "V&#46; Dubuc"
                            1 => "D&#46;F&#46; Moore"
                            2 => "L&#46;C&#46; Gioia"
                            3 => "G&#46; Saposnik"
                            4 => "D&#46; Selchen"
                            5 => "S&#46; Lanthier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jstrokecerebrovasdis.2012.10.005"
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                        "tituloSerie" => "J Stroke Cerebrovasc Dis"
                        "fecha" => "2013"
                        "volumen" => "22"
                        "paginaInicial" => "1288"
                        "paginaFinal" => "1292"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23168217"
                            "web" => "Medline"
                          ]
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                ]
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              "identificador" => "bib0495"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Natural history of the cerebrovascular complications of Fabry disease"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Mehta"
                            1 => "L&#46; Ginsberg"
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Pediatr Suppl"
                        "fecha" => "2005"
                        "volumen" => "94"
                        "paginaInicial" => "24"
                        "paginaFinal" => "27"
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                    ]
                  ]
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              "identificador" => "bib0500"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Fabry disease and factor V Leiden&#58; a potent vascular risk combination"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Tchan"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1445-5994.2011.02483.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intern Med J"
                        "fecha" => "2011"
                        "volumen" => "41"
                        "paginaInicial" => "422"
                        "paginaFinal" => "426"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21605293"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0505"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Thromboembolic events in Fabry disease and the impact of factor V Leiden"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Lenders"
                            1 => "N&#46; Karabul"
                            2 => "T&#46; Duning"
                            3 => "B&#46; Schmitz"
                            4 => "M&#46; Schelleckes"
                            5 => "R&#46; Mesters"
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                    0 => array:2 [
                      "doi" => "10.1212/WNL.0000000000001333"
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                        "tituloSerie" => "Neurology"
                        "fecha" => "2015"
                        "volumen" => "84"
                        "paginaInicial" => "1009"
                        "paginaFinal" => "1016"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25663229"
                            "web" => "Medline"
                          ]
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                  ]
                ]
              ]
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            36 => array:3 [
              "identificador" => "bib0510"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Profile of endothelial and leukocyte activation in Fabry patients"
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                          "etal" => true
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                            0 => "T&#46; DeGraba"
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                            3 => "E&#46; Brown"
                            4 => "B&#46; Bouti&#232;re"
                            5 => "G&#46; Altarescu"
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                  "host" => array:1 [
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                        "tituloSerie" => "Ann Neurol"
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                        "paginaInicial" => "229"
                        "paginaFinal" => "233"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10665494"
                            "web" => "Medline"
                          ]
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                ]
              ]
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            37 => array:3 [
              "identificador" => "bib0515"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "White matter lesion severity in male and female patients with Fabry disease"
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                          "etal" => false
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                            0 => "A&#46; Fellgiebel"
                            1 => "M&#46;J&#46; Muller"
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                            3 => "K&#46; Baron"
                            4 => "M&#46; Beck"
                            5 => "P&#46; Stoeter"
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Neurology"
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                        "paginaFinal" => "602"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16116124"
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              "identificador" => "bib0520"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry disease and the heart"
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                            4 => "F&#46; Weidemann"
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                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.beem.2014.10.003"
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                        "tituloSerie" => "Best Pract Res Clin Endocrinol Metab"
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                        "volumen" => "29"
                        "paginaInicial" => "195"
                        "paginaFinal" => "204"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25987173"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Electrocardiographic changes and arrhythmia in Fabry disease"
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Front Cardiovasc Med"
                        "fecha" => "2016"
                        "volumen" => "3"
                        "paginaInicial" => "7"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27047943"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Increased oxidative stress contributes to cardiomyocyte dysfunction and death in patients with Fabry disease cardiomyopathy"
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                  "host" => array:1 [
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                        "tituloSerie" => "Hum Pathol"
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                        "link" => array:1 [
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                    0 => array:2 [
                      "titulo" => "Fibrosis&#58; a key feature of Fabry disease with potential therapeutic implications"
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                        "tituloSerie" => "Orphanet J Rare Dis"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23915644"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "When foots come first&#58; early signs of podocyte injury in Fabry nephropathy without proteinuria"
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                        "tituloSerie" => "Nephron"
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                        "volumen" => "129"
                        "paginaInicial" => "3"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25592473"
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                ]
              ]
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            43 => array:3 [
              "identificador" => "bib0545"
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                    0 => array:2 [
                      "titulo" => "Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.ajkd.2007.12.032"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Kidney Dis"
                        "fecha" => "2008"
                        "volumen" => "51"
                        "paginaInicial" => "767"
                        "paginaFinal" => "776"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18436087"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Podocyte pathology and nephropathy &#8211; sphingolipids in glomerular diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Merscher"
                            1 => "A&#46; Fornoni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Front Endocrinol &#40;Lausanne&#41;"
                        "fecha" => "2014"
                        "volumen" => "5"
                        "paginaInicial" => "127"
                      ]
                    ]
                  ]
                ]
              ]
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            46 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Globotriaosylsphingosine actions on human glomerular podocytes&#58; implications for Fabry nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;D&#46; S&#225;nchez-Ni&#241;o"
                            1 => "A&#46;B&#46; Sanz"
                            2 => "S&#46; Carrasco"
                            3 => "M&#46;A&#46; Saleem"
                            4 => "P&#46;W&#46; Mathieson"
                            5 => "J&#46;M&#46; Valdivieso"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfq306"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nephrol Dial Transplant"
                        "fecha" => "2011"
                        "volumen" => "26"
                        "paginaInicial" => "1797"
                        "paginaFinal" => "1802"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20504837"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibici&#243;n de mTOR&#44; prote&#237;nas Akt y enfermedad renal cr&#243;nica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46; M&#225;rquez"
                            1 => "J&#46; Pascual"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3265/Nefrologia.pre2014.Apr.12381"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nefrolog&#237;a"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "425"
                        "paginaFinal" => "427"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25036055"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dysregulated autophagy contributes to podocyte damage in Fabry&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;C&#46; Liebau"
                            1 => "F&#46; Braun"
                            2 => "K&#46; H&#246;pker"
                            3 => "C&#46; Weitbrecht"
                            4 => "V&#46; Bartels"
                            5 => "R&#46;U&#46; M&#252;ller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2013"
                        "volumen" => "8"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Possible role of transforming growth factor-&#946;1 and vascular endothelial growth factor in Fabry disease nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;H&#46; Lee"
                            1 => "E&#46;N&#46; Choi"
                            2 => "Y&#46;J&#46; Jeon"
                            3 => "S&#46;C&#46; Jung"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/ijmm.2012.1139"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Mol Med"
                        "fecha" => "2012"
                        "volumen" => "30"
                        "paginaInicial" => "1275"
                        "paginaFinal" => "1280"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23007467"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease&#58; the European Fabry Working Group consensus document"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Biegstraaten"
                            1 => "R&#46; Arngr&#237;msson"
                            2 => "F&#46; Barbey"
                            3 => "L&#46; Boks"
                            4 => "F&#46; Cecchi"
                            5 => "P&#46;B&#46; Deegan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13023-015-0253-6"
                      "Revista" => array:5 [
                        "tituloSerie" => "Orphanet J Rare Dis"
                        "fecha" => "2015"
                        "volumen" => "10"
                        "paginaInicial" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25885911"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neuropathy and Fabry disease&#58; pathogenesis and enzyme replacement therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Schiffmann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Neurol Belg"
                        "fecha" => "2006"
                        "volumen" => "106"
                        "paginaInicial" => "61"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16898255"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Choi"
                            1 => "J&#46; Vernon"
                            2 => "O&#46; Kopach"
                            3 => "M&#46;S&#46; Minett"
                            4 => "K&#46; Milks"
                            5 => "P&#46;T&#46; Clayton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.neulet.2015.01.084"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurosci Lett"
                        "fecha" => "2015"
                        "volumen" => "594"
                        "paginaInicial" => "163"
                        "paginaFinal" => "168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25697597"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The cerebral vasculopathy of Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46;F&#46; Moore"
                            1 => "C&#46;R&#46; Kaneski"
                            2 => "H&#46; Askari"
                            3 => "R&#46; Schiffmann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jns.2007.01.053"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurol Sci"
                        "fecha" => "2007"
                        "volumen" => "257"
                        "paginaInicial" => "258"
                        "paginaFinal" => "263"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17362993"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fabry nephropaty&#58; a review &#8211; how can we optimize the management of Fabry nephropaty"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Waldek"
                            1 => "S&#46; Feriozzi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2369-15-72"
                      "Revista" => array:6 [
                        "tituloSerie" => "BMC Nephrol"
                        "fecha" => "2014"
                        "volumen" => "15"
                        "paginaInicial" => "72"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24886109"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NT-proBNP as prognostic biomarkers in Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Torralba-Cabeza"
                            1 => "S&#46; Olivera"
                            2 => "D&#46;A&#46; Hughes"
                            3 => "G&#46;M&#46; Pastores"
                            4 => "R&#46;N&#46; Mateo"
                            5 => "J&#46;I&#46; P&#233;rez-Calvo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ymgme.2011.06.021"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Genet Metab"
                        "fecha" => "2011"
                        "volumen" => "104"
                        "paginaInicial" => "301"
                        "paginaFinal" => "307"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21795086"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0610"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cystatin superfamily"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Ochieng"
                            1 => "G&#46; Chaudhuri"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1353/hpu.0.0257"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Health Care Poor Underserved"
                        "fecha" => "2010"
                        "volumen" => "21"
                        "paginaInicial" => "51"
                        "paginaFinal" => "70"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20173285"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0615"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Left ventricular geometry and blood pressure as predictors of adverse progression of Fabry cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Kr&#228;mer"
                            1 => "B&#46; Bijnens"
                            2 => "S&#46; St&#246;rk"
                            3 => "C&#46;O&#46; Ritter"
                            4 => "D&#46; Liu"
                            5 => "G&#46; Ertl"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0140627"
                      "Revista" => array:5 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2015"
                        "volumen" => "10"
                        "paginaInicial" => "e0140627"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26600044"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0620"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Successful management of enzyme replacement therapy in related Fabry disease patients with severe adverse events by switching from agalsidase Beta &#40;Fabrazyme<span class="elsevierStyleSup">&#174;</span>&#41; to agalsidase alfa &#40;Replagal<span class="elsevierStyleSup">&#174;</span>&#41;"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "K&#46; Tsuboi"
                            1 => "H&#46; Yamamoto"
                            2 => "F&#46; Somura"
                            3 => "H&#46; Goto"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/8904_2014_304"
                      "Revista" => array:6 [
                        "tituloSerie" => "JIMD Rep"
                        "fecha" => "2015"
                        "volumen" => "15"
                        "paginaInicial" => "105"
                        "paginaFinal" => "111"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24718841"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0625"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with Anderson&#8211;Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;J&#46; Coats"
                            1 => "V&#46; Parisi"
                            2 => "M&#46; Ramos"
                            3 => "K&#46; Janagarajan"
                            4 => "C&#46; O&#8217;Mahony"
                            5 => "A&#46; Dawnay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjcard.2012.08.055"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Cardiol"
                        "fecha" => "2013"
                        "volumen" => "111"
                        "paginaInicial" => "111"
                        "paginaFinal" => "117"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23040658"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0630"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enfermedad de Fabry"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Rodr&#237;guez-Palmero"
                            1 => "D&#46; Oliva"
                            2 => "G&#46; Pintos-Morell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "Diagn&#243;stico y tratamiento de las enfermedades metab&#243;licas hereditarias"
                        "paginaInicial" => "947"
                        "paginaFinal" => "959"
                        "edicion" => "4&#46;<span class="elsevierStyleSup">a</span> ed&#46;"
                        "serieFecha" => "2014"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0635"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Mauer"
                            1 => "E&#46; Glynn"
                            2 => "E&#46; Svarstad"
                            3 => "C&#46; T&#248;ndel"
                            4 => "M&#46;C&#46; Glubler"
                            5 => "West"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0112188"
                      "Revista" => array:5 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2014"
                        "volumen" => "9"
                        "paginaInicial" => "e112188"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25386848"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0640"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Plasma globotriaosylsphingosine as a biomarker of Fabry disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Togawa"
                            1 => "T&#46; Kodama"
                            2 => "T&#46; Suzuki"
                            3 => "K&#46; Sugawara"
                            4 => "T&#46; Tsukimura"
                            5 => "T&#46; Ohashi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ymgme.2010.03.020"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Genet Metab"
                        "fecha" => "2010"
                        "volumen" => "100"
                        "paginaInicial" => "257"
                        "paginaFinal" => "261"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20409739"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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Article information
ISSN: 22548874
Original language: English
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