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3.
PLoS One ; 15(1): e0227077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929594

RESUMO

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.


Assuntos
Modelos Animais de Doenças , Doença de Gaucher/genética , Glucosilceramidase/genética , Fenótipo , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Doença de Gaucher/metabolismo , Doença de Gaucher/patologia , Glucosilceramidase/metabolismo , Leucócitos/patologia , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Mutação , Neurônios/metabolismo , Neurônios/patologia , Baço/metabolismo , Baço/patologia , Timo/metabolismo , Timo/patologia
4.
BMC Med Genet ; 21(1): 12, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931749

RESUMO

BACKGROUND: Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. METHODS: Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. RESULTS: Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. CONCLUSIONS: Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.


Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Vitamina B 12/metabolismo , beta-Glucosidase/genética , Técnicas de Cultura de Células , Feminino , Fibroblastos/metabolismo , Doença de Gaucher/metabolismo , Doença de Gaucher/patologia , Homocisteína/metabolismo , Humanos , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Ácido Metilmalônico/metabolismo , Mutação , Fenótipo , Saposinas/genética , Transcobalaminas/metabolismo
5.
Am J Hematol ; 95(5): 483-491, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31990411

RESUMO

Gaucher disease (GD) is a recessively inherited lysosomal storage disorder in which sphingolipids accumulates in the macrophages that transform into Gaucher cells. A growing body of evidence indicates that red blood cells (RBCs) represent important actors in GD pathophysiology. We previously demonstrated that altered RBC properties including increased Lyso-GL1 levels, dyserythropoiesis, and iron metabolism defect in GD patients contribute to anemia and hyperferritinemia. Since RBC defects also correlated well with markers of GD severity and were normalized under enzyme replacement therapy (ERT), the identification of molecules that are deregulated in GD RBCs represents an important issue in the search of pertinent markers of the disease. Here, we found a decreased expression of the GPI-anchored cell surface protein Semaphorin 7A (Sema7A) in RBCs from untreated GD (GD UT) patients, in parallel with increased levels of the soluble form in the plasma. Sema7A plays a role in neural guidance, atherosclerosis, and inflammatory diseases and represents a promigratory cue in physiological and pathological conditions. We showed that the decreased expression of Sema7A in RBCs correlated with their abnormal properties and with markers of GD activity. Interestingly, ERT restored the level of Sema7A to normal values both in RBCs and in plasma from GD patients. We then proposed that SemaA7A represents a simple and pertinent marker of inflammation in GD. Finally, because Sema7A is known to regulate the activity of immune cells, the increased level of soluble Sema7A in GD patients could propagate inflammation in several tissues.


Assuntos
Doença de Gaucher/tratamento farmacológico , Semaforinas/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estudos Prospectivos , Semaforinas/farmacologia
6.
Eur Arch Paediatr Dent ; 21(2): 241-247, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31531808

RESUMO

PURPOSE: Gaucher disease (GD) is a lysosomal storage disease caused by an autosomal recessive inherited deficiency of the lysosomal enzyme glucocerebrosidase. The aim of this study is to describe jaw bones' involvement and dental radiographic features in paediatric Gaucher disease patients (type I and type III). METHODS: The study population of this case-control study included: 42 Gaucher patients (study group) and 84 medically free children (control group). The radiographic images of both groups were analysed for the following findings: generalised bone rarefaction, localised rarefaction and enlarged bone marrow spaces, thinning of cortex, pseudocystic radiolucent lesions, anodontia and dental anomalies. Dental age assessment of Gaucher patients using the Demirjian's method was also performed. RESULTS: Generalised rarefaction showed almost similar percentages in both types of Gaucher disease cases. Localised rarefaction was noted in 30.77% and 18.75% of Gaucher disease type III and type I, respectively. Pseudocystic radiolucent lesions, thinning of cortex, anodontia and dental anomalies were more prevalent in type III Gaucher patients. The mean chronological and mean dental ages in both sexes of Gaucher patients were not statistically significant. CONCLUSION: Thinning of cortex, localised rarefaction and generalised rarefaction are the most common jaw bone findings in Gaucher patients.


Assuntos
Doença de Gaucher , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino
8.
J Pharm Biomed Anal ; 177: 112858, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31518862

RESUMO

Eliglustat is an oral substrate reduction therapy drug and has been approved as a first-line treatment for adults with Gaucher disease type 1 (GD 1). In the present study, we aimed to develop and establish an accurate and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the measurement of eliglustat concentration in rat plasma. The goal of chromatographic separation of eliglustat and the internal standard (bosutinib) was finished on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column. Acetonitrile and 0.1% formic acid in water were employed as the mobile phase in a mode of gradient elution with the 0.40 mL/min flow rate. The detection was carried out on a XEVO TQ-S triple quadrupole tandem mass spectrometer coupled with electrospray ionization (ESI) interface in the positive-ion mode. Multiple reaction monitoring (MRM) was used to monitor the precursor-to-product ion transitions of m/z 405.4 → 84.1 for eliglustat and m/z 530.2 → 141.2 for bosutinib (IS), respectively. It was found that the linearity of the method in the range of 1-500 ng/mL was good for eliglustat. The values of intra- and inter-day accuracy and precision were all within the acceptance limits, and no matrix effect was found in this method. The current developed method was further performed to support in vivo pharmacokinetic study of eliglustat after oral treatment with 10 mg/kg eliglustat to rats.


Assuntos
Monitoramento de Medicamentos/métodos , Inibidores Enzimáticos/farmacocinética , Doença de Gaucher/tratamento farmacológico , Pirrolidinas/farmacocinética , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/sangue , Animais , Cromatografia Líquida de Alta Pressão/métodos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Estudos de Viabilidade , Humanos , Limite de Detecção , Masculino , Nitrilos/administração & dosagem , Nitrilos/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/sangue , Quinolinas/administração & dosagem , Quinolinas/sangue , Ratos , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
10.
Blood Cells Mol Dis ; 80: 102373, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31718920

RESUMO

Gaucher disease is an inherited lysosomal storage disease commonly associated with hepatosplenomegaly and cytopenias. Progressive cytopenias may be interpreted as an indication of advanced disease and suggest the need to start Gaucher disease specific treatment. As bone marrow evaluation is not routinely performed in Gaucher disease, other causes of cytopenias such as myelodysplastic syndrome a stem cell disorder may be missed. Six patients are described who suffered simultaneously from Gaucher disease and myelodysplastic syndrome, with a discussion of the diagnostic challenges.


Assuntos
Doença de Gaucher/complicações , Doença de Gaucher/diagnóstico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancitopenia/patologia
11.
Neurology ; 93(24): e2272-e2283, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31719137

RESUMO

OBJECTIVE: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center. METHODS: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator. RESULTS: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ. CONCLUSIONS: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.


Assuntos
Cognição , Doença de Gaucher , Inteligência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Valores de Referência , Estudos Retrospectivos , Escalas de Wechsler , Adulto Jovem
12.
Clin Appl Thromb Hemost ; 25: 1076029619889685, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31775513

RESUMO

Gaucher disease (GD) is one of the most important lysosomal storage disorders. T-lymphocytes perform and regulate many of the immune processes and play a major role in immune homeostasis. Studies have shown that GD causes impairment in T-lymphocyte functions, although the role and status of T-lymphocytes in GD are still under investigation. It is still not fully known how GD leads to the altered biochemical and immunological cellular functions observed in the disease. Our study aimed to evaluate the variations of regulatory T-lymphocytes (Tregs) in 20 Egyptian children with GD under enzyme replacement therapy, managed in Assiut University Hospitals. Tregs were detected using 3-color flow cytometric immunophenotyping, in which subpopulations of T-lymphocytes and the expression of CD4+ on their surfaces were gated. The expression of CD25+ was assessed on CD4+ cells with different gates to define CD4+CD25, CD4+CD25+high, and CD4+CD25+ low cells. Then, CD4+CD25+highFoxp3+cells and MFI of Foxp3+ expression on CD4+CD25+ high were determined. We found the levels of CD4+CD25+/CD4+, CD4+CD25+high/CD4+, CD4+CD25+highFoxp3+ Tregs, and median fluorescence intensity of Foxp3+ expression on CD4+CD25+high were significantly lower in children with GD compared to healthy controls. In conclusion, our data showed significantly decreased regulatory T-lymphocytes in children with GD. The reduced effect of Tregs may have a role in the pathogenesis of immune dysregulation in children with GD. The relationship of these cells to immune disorders in GD children remains to be determined. Therefore, we recommend further studies to elucidate the role and function of Tregs in GD and its potential role in the disease phenotype, as well as how it is affected by electrical resistivity tomography.


Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Gaucher/genética , Linfócitos T Reguladores/metabolismo , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Regulação para Baixo , Feminino , Doença de Gaucher/tratamento farmacológico , Humanos , Masculino
13.
Int J Mol Sci ; 20(23)2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31771289

RESUMO

Sphingolipidoses are inherited genetic diseases characterized by the accumulation of glycosphingolipids. Sphingolipidoses (SP), which usually involve the loss of sphingolipid hydrolase function, are of lysosomal origin, and represent an important group of rare diseases among lysosomal storage disorders. Initial treatments consisted of enzyme replacement therapy, but, in recent decades, various therapeutic approaches have been developed. However, these commonly used treatments for SP fail to be fully effective and do not penetrate the blood-brain barrier. New approaches, such as genome editing, have great potential for both the treatment and study of sphingolipidoses. Here, we review the most recent advances in the treatment and modelling of SP through the application of CRISPR-Cas9 genome editing. CRISPR-Cas9 is currently the most widely used method for genome editing. This technique is versatile; it can be used for altering the regulation of genes involved in sphingolipid degradation and synthesis pathways, interrogating gene function, generating knock out models, or knocking in mutations. CRISPR-Cas9 genome editing is being used as an approach to disease treatment, but more frequently it is utilized to create models of disease. New CRISPR-Cas9-based tools of gene editing with diminished off-targeting effects are evolving and seem to be more promising for the correction of individual mutations. Emerging Prime results and CRISPR-Cas9 difficulties are also discussed.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Esfingolipidoses/terapia , Animais , Modelos Animais de Doenças , Terapia de Reposição de Enzimas , Doença de Gaucher/genética , Doença de Gaucher/terapia , Humanos , Esfingolipidoses/genética , beta-Glucosidase/genética
14.
J Orthop Surg Res ; 14(1): 383, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752949

RESUMO

BACKGROUND: Chronic fatigue (CFg) is a prevalent symptom in Gaucher disease (GD) at diagnosis (79%) and remains in a quarter of patients after years of therapy. Bone abnormalities are present in over 70% and peripheral neuropathy in about 11% of the patients, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors such as muscle-tendinous weakness could have influence in the development of CFg. METHODS: We have evaluated the fiber structure and elasticity of muscle-tendinous unit by strain-elastography (S-ELA) and analyzed their influence in the CFg. S-ELA study was performed in Achilles tendon in 25 type 1 and two type 3 GD patients, all of them with fatigue and were on enzymatic replacement therapy for mean 13 years; simultaneously, bone marrow burden by MRI and calcaneus ultrasound densitometry were evaluated. Blood cell counts, plasma biomarkers, GBA1 genotyping, and SF36 quality of life scale (QoL) were also performed. STATISTICAL ANALYSIS: descriptive and comparative test. RESULTS: All patients showed a normal Achilles tendinous structure. Abnormal stiff grade 2-3 was found in 17/27 (62.9%); in 11/27 (40.7%) of patients, the alteration was bilateral. There were no correlations between the S-ELA results to other variables; nevertheless, a significant correlation between the degree of tendon hardness and the low score on the QoL scales (p = 0.0035) was found. The S-ELA is a sensitive painless, fast, and low cost method to detect muscle-tendinous subclinical dysfunction that could contribute to CFg in GD. The identification of subclinical tendon alteration would be a sign of alarm, focused on the risk of development of bone complications. CONCLUSION: Intratendinous alteration in strain-elastography is an independent variable in GD patients with persistent fatigue.


Assuntos
Tendão do Calcâneo/fisiopatologia , Síndrome de Fadiga Crônica/etiologia , Doença de Gaucher/complicações , Tendão do Calcâneo/diagnóstico por imagem , Adolescente , Adulto , Estudos de Casos e Controles , Estudos Transversais , Técnicas de Imagem por Elasticidade , Síndrome de Fadiga Crônica/diagnóstico por imagem , Síndrome de Fadiga Crônica/fisiopatologia , Feminino , Doença de Gaucher/diagnóstico por imagem , Doença de Gaucher/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Adulto Jovem
15.
Mymensingh Med J ; 28(4): 949-951, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31599267

RESUMO

Gaucher's disease is one of the important storage disorders. It belongs to the lysosomal storage disorders group. There is defective activity of an enzyme named ß-glucosidase which ultimately renders the cell of macrophage lineage loaded with glucocerebrosides. There is multi-organ involvement that manifests as hepatosplenomegaly, variable cytopenias, skeletal disorders, neurological features etc. When serum ß-glucosidase level is below 15% of mean normal activity Gaucher's disease is confirmed. Enzyme replacement is the definitive treatment. Here we report a case of type 1 or non-neuropathic form Gauchers disease presented with feeling of a lump in left upper abdomen and progressive generalized weakness and hepatosplenomegaly. Her complete blood count revealed pancytopenia and bone trephine biopsy showed Gaucher's cells. Diagnosis and management may be delayed as this disease is rare. Clinical and bone marrow examination is the mainstay of diagnosis. So emphasis should be given in this regard.


Assuntos
Doença de Gaucher , Pancitopenia , Adulto , Biópsia , Feminino , Humanos , Baço , Esplenomegalia , Adulto Jovem
19.
Hum Mol Genet ; 28(20): 3406-3421, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31373366

RESUMO

Gaucher disease (GD) is caused by GBA1 mutations leading to functional deficiency of acid-ß-glucosidase (GCase). No effective treatment is available for neuronopathic GD (nGD). A subclass of neural stem and precursor cells (NPCs) expresses VLA4 (integrin α4ß1, very late antigen-4) that facilitates NPC entry into the brain following intravenous (IV) infusion. Here, the therapeutic potential of IV VLA4+NPCs was assessed for nGD using wild-type mouse green fluorescent protein (GFP)-positive multipotent induced pluripotent stem cell (iPSC)-derived VLA4+NPCs. VLA4+NPCs successfully engrafted in the nGD (4L;C*) mouse brain. GFP-positive cells differentiated into neurons, astrocytes and oligodendrocytes in the brainstem, midbrain and thalamus of the transplanted mice and significantly improved sensorimotor function and prolonged life span compared to vehicle-treated 4L;C* mice. VLA4+NPC transplantation significantly decreased levels of CD68 and glial fibrillary acidic protein, as well as TNFα mRNA levels in the brain, indicating reduced neuroinflammation. Furthermore, decreased Fluoro-Jade C and NeuroSilver staining suggested inhibition of neurodegeneration. VLA4+NPC-engrafted 4L;C* midbrains showed 35% increased GCase activity, reduced substrate [glucosylceramide (GC, -34%) and glucosylsphingosine (GS, -11%)] levels and improved mitochondrial oxygen consumption rates in comparison to vehicle-4L;C* mice. VLA4+NPC engraftment in 4L;C* brain also led to enhanced expression of neurotrophic factors that have roles in neuronal survival and the promotion of neurogenesis. This study provides evidence that iPSC-derived NPC transplantation has efficacy in an nGD mouse model and provides proof of concept for autologous NPC therapy in nGD.


Assuntos
Doença de Gaucher/metabolismo , Doença de Gaucher/terapia , Glucosilceramidase/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Neurais/fisiologia , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Infusões Intravenosas , Integrina alfa4beta1/metabolismo , Camundongos , Células-Tronco Neurais/citologia , beta-Glucosidase/metabolismo
20.
J Pediatr Hematol Oncol ; 41(7): e416-e420, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31385859

RESUMO

Gaucher disease (GD) is the most common lysosomal storage disorder, the aim of the current study was to investigate hyperimmunoglobulinemia and abnormalities of serum immunoglobulin G (IgG) subclasses in children with GD and the relation of those findings to the GD phenotype and genotype, duration of enzyme replacement therapy (ERT), and infection frequency. The study included 20 Egyptian children with GD receiving ERT and 20 age-matched and sex-matched healthy children as controls. Serum Ig and serum IgG subclass levels were measured in the children with GD. Serum IgG subclass levels were measured in the control subjects. Hyperimmunoglobulinemia was present in 15 of the 20 (75%) children with GD. In addition, it is found significantly lower IgG2 levels and significantly higher IgG3 levels in the GD group than in the control group (P<0.001 and <0.006, respectively). Patients with 12 infections per year had significantly higher IgG3 levels compared with patients with 6 infections per year (P=0.022). In conclusion, hyperimmunoglobulinemia and IgG subclass abnormalities occur in children with GD who are on ERT and may be related to recurrent infections.


Assuntos
Doença de Gaucher/complicações , Doença de Gaucher/imunologia , Hipergamaglobulinemia/imunologia , Imunoglobulina G/imunologia , Adolescente , Criança , Pré-Escolar , História do Século XV , Humanos , Lactente , Masculino
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