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Background MOG-IgG-associated disease (MOGAD) in adults typically presents as a monophasic or relapsing optic, spinal, or opticospinal neuroinflammatory syndrome. Current recommendations discourage testing for MOG-IgG in patients with clinical or paraclinical findings more typical of MS, or in patients with a progressive clinical course. However, this approach may impede identification of the full phenotypic spectrum of this recently described disorder. Methods We retrospectively reviewed charts of 39 MOG-IgG-seropositive patients from two Ohio-based neuroimmunology centers to identify unusual disease patterns. Those with a progressive course were included in this case series. Results We describe five cases of progressive myelopathy associated with MOG-IgG. Most patients had features suggestive of MS, including typical MRI and cerebrospinal fluid findings. However, MOG-IgG positive patients with progressive myelopathy showed poor response to MS disease modifying therapy and better response to intravenous immunoglobulins similar to previous reports on MOGAD patients. Conclusion MOG-IgG-seropositive patients may present with progressive myelopathy and may have a clinical and radiologic phenotype suggestive of primary progressive or secondary progressive MS, or progressive solitary sclerosis. MOG-IgG testing should be considered in patients with progressive myelopathy, especially if clinically worsening on MS therapy.
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Esclerose Múltipla , Neuromielite Óptica , Doenças da Medula Espinal , Adulto , Aquaporina 4 , Autoanticorpos , Humanos , Glicoproteína Mielina-Oligodendrócito , Ohio , Estudos RetrospectivosRESUMO
BACKGROUND: This case series describes the use of the Medtronic Micro Vascular Plug (MVP) system in the treatment of acute massive orofacial hemorrhages in patients with cancer and trauma, resulting in successful hemostasis in these emergent cases. CASE DESCRIPTION: The first case describes a patient who presented with life-threatening oropharyngeal hemorrhage after a motor vehicle accident. In the second case, a patient with oropharyngeal cancer presented with life-threatening bleeding from an ulcerated tumor. Patients were successfully treated with a combination of MVP and coils. Immediate postprocedural imaging confirmed that homeostasis was achieved. CONCLUSIONS: These cases demonstrate that the MVP as an embolic device is a valuable transarterial embolic treatment option in cases of acute orofacial bleeding where rapid, effective hemostasis is required.
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Procedimentos Endovasculares/instrumentação , Hemorragia/cirurgia , Orofaringe/lesões , Instrumentos Cirúrgicos , Acidentes de Trânsito , Adulto , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/métodos , Hemorragia/etiologia , Humanos , Hipotensão , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/complicações , Doenças Faríngeas/etiologia , Doenças Faríngeas/cirurgia , Índice de Gravidade de Doença , Fraturas Cranianas , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Resultado do TratamentoRESUMO
Therapeutic monoclonal antibodies have the potential to work as biological therapeutics. OKT3, Herceptin, Keytruda and others have positively impacted healthcare. Antibodies evolved naturally to provide high specificity and high affinity once mature. These characteristics can make them useful as therapeutics. However, we may be missing characteristics that are not obvious. We present a means of measuring antibodies in an unbiased manner that may highlight therapeutic activity. We propose using a microarray of random peptides to assess antibody properties. We tested twenty-four different commercial antibodies to gain some perspective about how much information can be derived from binding antibodies to random peptide libraries. Some monoclonals preferred to bind shorter peptides, some longer, some preferred motifs closer to the C-term, some nearer the N-term. We tested some antibodies with clinical activity but whose function was blinded to us at the time. We were provided with twenty-one different monoclonal antibodies, thirteen mouse and eight human IgM. These antibodies produced a variety of binding patterns on the random peptide arrays. When unblinded, the antibodies with polyspecific binding were the ones with the greatest therapeutic activity. The protein target to these therapeutic monoclonals is still unknown but using common sequence motifs from the peptides we predicted several human and mouse proteins. The same five highest proteins appeared in both mouse and human lists.
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Anticorpos Monoclonais/análise , Mapeamento de Epitopos/métodos , Biblioteca de Peptídeos , Análise Serial de Proteínas , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/metabolismo , Especificidade de Anticorpos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Imunoglobulina M/análise , Imunoglobulina M/metabolismo , Camundongos , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Análise Serial de Proteínas/métodos , Ligação Proteica , Proteoma/análiseRESUMO
Narcolepsy (NA) is a primary sleep disorder characterized by loss of hypocretinergic/orexinergic neurons. NA is associated with an increased risk for metabolic disorders such as diabetes mellitus (DM). Proposed mechanisms for this association are alterations in food intake, disruption of energy balance, glucose tolerance, and insulin sensitivity, as well as inflammation and genetic factors. Orexin deficiency, is associated with increased food intake and reduced basal metabolic rate (BMR) both leading to obesity. The anti-apoptotic effect of orexin on pancreatic beta-cells, increase in peripheral insulin sensitivity, and reduced lipolysis in the adipose tissue, together confer an increased risk for obesity and type 2 DM (T2DM) in NA patients. The main pathomechanisms relating type 1 DM (T1DM) to NA involve autoimmunity and inflammation. HLA genes that confer a risk for NA, such as DQB1*0602 are protective against T1DM, while catepsin gene (CTSH) mutations are a risk factor for both NA and T1DM. Gestational DM (GDM) is associated with obesity which is a potential outcome of narcolepsy. GDM patients have lower serum orexin expression which is associated with increased fasting glucose and decreased fasting insulin. Ongoing research on the use of orexin receptor (OXR) antagonists in sleep disorders has opened a window to the pathomechanisms of NA and the potentials for OXR modulation in eating disorders and obesity. Understanding the common pathophysiological mechanisms of NA, DM and obesity could guide us in designing life-style modification programs, genetic consultations, and targeted therapies, such as immunotherapy, for obesity in NA.
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Diabetes Mellitus/fisiopatologia , Narcolepsia/fisiopatologia , Orexinas/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo Energético , Humanos , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Narcolepsia/metabolismo , Neurônios/metabolismo , Obesidade/fisiopatologiaRESUMO
Schizophrenia, a multisystem disorder with an unknown etiology, is associated with several immune dysfunctions, including abnormal levels of circulating cytokines. In this review, we investigated the changes of cytokines in schizophrenic patients, their connection with behavioral symptoms severity and their potential clinical implications. We also assessed the possible causative role of abnormal cytokine levels in schizophrenia pathogenesis. Based on meta-analyses, we categorized cytokines according to their changes in schizophrenic patients into four groups: (1) increased cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1ß, IL-12, and transforming growth factor (TGF)-ß, (2) non-altered cytokines, including IL-2, IL-4, and IL-17, (3) increased or non-altered cytokines, including IL-8 and interferon (IFN)-γ, and (4) IL-10 with increased, decreased, and non-altered levels. Notably, alterations in cytokines may be variable in four different categories of SP, including first-episode and drug-naïve, first-episode and non-drug-naïve, stable chronic, and chronic in acute relapse. Furthermore, disease duration, symptoms severity, incidence of aggression, and cognitive abilities are correlated with levels of certain cytokines. Clinical implications of investigating the levels of cytokine in schizophrenic patients include early diagnosis, novel therapeutic targets development, patient stratification for choosing the best therapeutic protocol, and predicting the prognosis and treatment response. The levels of IL-6, IL-8, IFN-γ, IL-2 are related to the treatment response. The available evidence shows a potential causative role for cytokines in schizophrenia development. There is a substantial need for studies investigating the levels of cytokines before disease development and delineating the therapeutic implications of the disrupted cytokine levels in schizophrenia.
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Inflammatory elements and genetics have major roles in febrile seizures (FS) pathogenesis. Seventy patients were enrolled and compared with 139 controls. The allele and genotype frequency of the IL-2 gene at -330 and +166 positions and the IFN-γ at +874 position were determined. A significant positive association with GG genotype at position -330 in the patient group was found (P=0.003). Further, a positive association was detected in simple and complex FS groups at the same position (P=0.03, P=0.004). IL-2 GT haplotype was significantly more common in the patients compared to controls (P=0.0008). Higher frequency of GT haplotype was detected in simple FS patients in comparison to controls (P=0.0003). Contrary, IL-2 TG haplotype frequency was lower in complex FS group (P=0.005). Overrepresentation of certain alleles, genotypes and haplotypes in IL-2 gene in FS patients could predispose individuals to this disease.
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Predisposição Genética para Doença , Interferon gama/genética , Interleucina-2/genética , Convulsões Febris/genética , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Parkinson's disease (PD) is histologically characterized by the accumulation of α-synuclein particles, known as Lewy bodies. The second most common neurodegenerative disorder, PD is widely known because of the typical motor manifestations of active tremor, rigidity, and postural instability, while several prodromal non-motor symptoms including REM sleep behavior disorders, depression, autonomic disturbances, and cognitive decline are being more extensively recognized. Motor symptoms most commonly arise from synucleinopathy of nigrostriatal pathway. Glutamatergic, γ-aminobutyric acid (GABA)ergic, cholinergic, serotoninergic, and endocannabinoid neurotransmission systems are not spared from the global cerebral neurodegenerative assault. Wide intrabasal and extrabasal of the basal ganglia provide enough justification to evaluate network circuits disturbance of these neurotransmission systems in PD. In this comprehensive review, English literature in PubMed, Science direct, EMBASE, and Web of Science databases were perused. Characteristics of dopaminergic and non-dopaminergic systems, disturbance of these neurotransmitter systems in the pathophysiology of PD, and their treatment applications are discussed.
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Neurotransmissores/classificação , Doença de Parkinson/metabolismo , Transmissão Sináptica , Animais , Humanos , Neurotransmissores/metabolismo , Doença de Parkinson/etiologiaRESUMO
Through selective activation/inhibition or dissection of neuronal circuits, optogenetic tools have raised hopes for a better understanding of neuropsychiatric mechanisms and therapeutic targets for various disorders. Although, overcoming serious limitations result in from conventional neuronal circuit study, this method has its own imperfections, such as optogenetic modulation of neural activity, using an internal, animal-generated, light source. In this review, limitations of external light delivery systems and possible approaches for using internal light sources in laboratory animals and perhaps, human being, are being addressed.
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Encéfalo/metabolismo , Proteínas Luminescentes/análise , Dispositivos Ópticos , Optogenética/métodos , Animais , Encéfalo/patologia , Humanos , Medições Luminescentes/instrumentação , Medições Luminescentes/métodos , Proteínas Luminescentes/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Neurônios/metabolismo , Neurônios/patologia , Optogenética/instrumentação , Engenharia de Proteínas/métodosRESUMO
Neuromyelitis optica (NMO) and the associated NMO spectrum disorders are demyelinating disorders affecting the spinal cord and optic nerves. It has prominent female predominance and many of these patients are in their childbearing years. As pregnancy seems to have a major impact on this disease course, in this review, recent studies with a focus on this disease and pregnancy and safety of available treatment options during this period are discussed.
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Neuromielite Óptica , Complicações na Gravidez , Feminino , Humanos , GravidezRESUMO
Interleukin-1 (IL-1) plays a key role in inflammation, has an effect on a wide variety of cells, and often leads to tissue destruction. While the ratio between IL-1 and IL-1Ra could influence the development of different diseases of the central nervous system, its gene polymorphisms were investigated in a group of patients with febrile seizures. Ninety patients with febrile seizures were enrolled and compared with 140 controls. The allele and genotype frequency of single nucleotide polymorphisms within the IL-1α, ß, IL-1 R and IL-1Ra gene were determined. The frequency of the IL-1Ra/C allele at position Mspa-I 11100 was decreased significantly (P= .002) and the IL-1Ra/T frequency was significantly increased in patients (P= .002). In addition, the CT genotype frequency at the same position was significantly overrepresented in controls compared to patients (P= .001). Certain alleles and genotypes in the IL-1 gene were overrepresented in patients with febrile seizures, which possibly could predispose individuals to this disease.
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Predisposição Genética para Doença/genética , Interleucina-1/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-1/genética , Convulsões Febris/genética , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Razão de ChancesRESUMO
Multiple sclerosis is a chronic immune-mediated disease of the nervous system. In the early disease course, axonal loss and neurodegeneration occurs that could possibly lead to irreversible neurological impairments. Preventing brain atrophy may have important clinical implications affecting treatment decisions in the future. In recent years, research efforts have directed towards finding agents to modify the disease and reduce brain volume loss. Intravenous immunoglobulin (IVIg) may have some potential roles in this regard.
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Encéfalo/diagnóstico por imagem , Imunoglobulinas Intravenosas/uso terapêutico , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Humanos , RadiografiaRESUMO
Febrile seizures (FS) is the most common seizure disorder during childhood. This study was performed in 78 patients with FS and 137 control subjects to assess polymorphisms of the TNF-α gene at positions -308 and -238, using the polymerase chain reaction and the sequence specific primers method. The highest positive allelic association that made the patients susceptible to FS was seen for TNF-α -238/G (p<0.0001). The GG genotype at TNF-α -238 was significantly higher in the patients with FS, compared to the controls (p=0.0001). Also, GA genotype at the same position was significantly lower in patients than in controls (P=0.0001). The GG haplotype had a significant positive association at TNF-α (308, 238) while GA haplotype showed a negative association (P<0.001). Our data support the idea that TNF-α single-nucleotide polymorphisms play a role in the pathogenesis of FS.
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Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Convulsões Febris/genética , Fator de Necrose Tumoral alfa/genética , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , MasculinoRESUMO
PURPOSE: Febrile seizures (FS) are the most common convulsive event in children. Inflammatory elements and genetics seem to have major roles in their pathogenesis. METHODS: Seventy nine patients with FS were enrolled in this study and compared with 140 controls. Cytokine genotyping was performed, using polymerase chain reaction with sequence-specific primers. The allele and genotype frequency of three single nucleotide polymorphisms (SNPs) within the IL-10 gene at -1082, -819 and -592 positions (rs1800896, rs1800871, rs1800872), and two SNPs within the TGFB at codons 10 and 25 (rs1982037, rs1800471) were determined. RESULTS: No significant difference was detected in allelic frequency of IL-10 at -1082, -819 and -592 positions (rs1800896, rs1800871, rs1800872) and TGFB at codon 25 (rs1800471), between patients and controls. A significant negative association was observed at the codon 10/CT (rs1982037) in the patient group (OR, 0.5; 95%CI, 0.27-0.93; p=0.026). Further, a negative association was detected in patients with simple FS at same position (OR, 0.41; 95%CI, 0.18-0.93; p=0.03), thus revealing a protective effects in FS patients. There was no significant difference in allelic and genotype frequency between simple and complex FS samples. Furthermore, haplotype analysis revealed significant difference in frequency of TGFB/TC haplotype in comparison between complex FS patients and controls (p=0.048). CONCLUSION: Certain alleles, genotypes, and haplotypes in TGFB genes were over represented in patients with FS, which possibly could predispose individuals to this disease.
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Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Convulsões Febris/genética , Fator de Crescimento Transformador beta1/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Lactente , Irã (Geográfico)RESUMO
Autophagy is a vesicle and lysosome-mediated degradative pathway that is essential for protein homeostasis and cell health. In particular, compared to nonneuronal cells, neurons are dependent on high basal autophagy for survival. There is emerging agreement that defects in autophagy are likely to contribute to the neurodegenerative processes in numerous diseases, including Alzheimer's disease (AD). Autophagy-lysosome defects occur early in the pathogenesis of AD and have been proposed to be a significant contributor to the disease process. Given the fact that autophagy deficits are likely major contributors to the etiology of AD, the focus of this review will be on recent studies that support a role for autophagy deficits in AD.
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Doença de Alzheimer/patologia , Autofagia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Autofagia/fisiologia , Humanos , Proteínas tau/metabolismoRESUMO
As of importance of interleukin-4 (IL-4) in inhibiting the production of proinflammatory cytokines, the IL4 gene polymorphisms were investigated in patients with febrile seizure. This association has not been investigated yet, except 1 study which has been done in Japanese population. Eighty-two patients with febrile seizure were enrolled in this study, compared with 139 controls. The allele and genotype frequency of 3 single-nucleotide polymorphisms of IL4 gene were determined. Frequency of the IL4-590/C allele in the patient group was significantly higher than in the control group (P < .0001). Frequency of the following genotypes was significantly lower in patients compared to controls: IL-4 (-590) TC (P = .0001) and IL-4 (-33) TC (P = .001). The most frequent IL-4 haplotype in the patient group was TCC (P = .00) haplotype. In contrast, frequencies of GCC (P = .01), TTT (P = .009), and TTC (P = .0007) haplotypes were significantly lower in febrile seizure patients. Certain alleles, genotypes, and haplotypes in the IL4 gene were overrepresented in Iranian patients with febrile seizure, which could predispose individuals to this disease, and further investigations in other ethnicities are required.
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Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Convulsões Febris/genética , Criança , Pré-Escolar , Frequência do Gene , Técnicas de Genotipagem , Haplótipos , Humanos , Lactente , Irã (Geográfico)RESUMO
Neuromyelitis optica is an inflammatory demyelinating disease (IDD) of the CNS, which mainly affects optic nerve and spinal cord. Autoantibodies against aquaporin-4 also known as NMO-IgG have been implicated in the pathogenesis of NMO. We evaluated the sensitivity and specificity of NMO-IgG assay for diagnosing NMO patients and differentiating them from MS patients and those with undifferentiated IDD with overlap symptoms.Eligibility of patients with demyelinating disorders was evaluated based on physical examination, laboratory and imaging studies. Thirty four definite NMO patients (disregarding NMO-IgG status), 34 multiple sclerosis (MS) patients with a history of optic neuritis (ON) or myelitis that were matched for age and disease activity and 44 patients with ON or myelitis attacks fulfilling neither criteria of MS or NMO (NMO spectrum) were selected as undifferentiated group. NMO-IgG was measured in the serum of the included patients by cell-based indirect immunofluorescence assay (IFA). NMO antibody was positive in 11 (32.3%), and 4 (9.09%) patients in NMO and undifferentiated groups, but was undetctable in MS patients. NMO antibody was 32% (95%Cl: 19-49%) sensitive in detecting NMO patients. Its specificity in differentiating NMO from MS subjects was 100 % (95% Cl: 90-!00%). NMO antibody was 95% (95% Cl: 0.88-0.98) specific in differentiating NMOs from other demyelinating diseases. Our results showed that although NMO antibody is highly specific for NMO, current method of measuring it with cell-based IFA is not highly sensitive for diagnosing NMO patients.
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Autoanticorpos/sangue , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Imunoglobulina G/sangue , Neuromielite Óptica/diagnóstico , Adulto , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/sangue , Diagnóstico Diferencial , Feminino , Técnica Indireta de Fluorescência para Anticorpo/métodos , Humanos , Irã (Geográfico) , Masculino , Neuromielite Óptica/sangue , Neuromielite Óptica/imunologia , Sensibilidade e Especificidade , Estudos SoroepidemiológicosRESUMO
Febrile seizures (FSs) are the most common convulsive event in children. Inflammatory elements and genetics have major roles in their pathogenesis. As of the importance of interleukin-6 (IL-6) in FS, this study was performed to assess IL6 single nucleotide polymorphisms (SNPs) in a group of patients with FS. IL6 gene (-174 and +565) SNPs were studied on genomic DNAs of 90 children with FS, using PCR-SSP method. The results were compared to 139 healthy individuals. The presence of the G allele or the GG genotype at +565 position reduced risk of FS, while the A allele at +565 position of the promoter regions was a constituted risk factor for developing FS. This study could support the idea that IL6 SNPs play a role in the pathogenesis of FS.
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Interleucina-6/genética , Polimorfismo de Nucleotídeo Único/genética , Convulsões Febris/genética , Alelos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Lactente , Masculino , Regiões Promotoras Genéticas/genéticaRESUMO
OBJECTIVE: About one third of partial seizures are refractory to treatment. Several anticonvulsant drugs have entered the market in recent decades but concerns about intolerance, drug interactions, and the safety of the drug are notable. One of these new anticonvulsants is pregabalin, a safe drug with almost no interaction with other antiepileptic drugs. METHODS: In this open label clinical trial study, pregabalin was used for evaluation of its efficacy on reducing seizure frequency in 29 children suffering from refractory partial seizures. Average daily and weekly seizure frequency of the patients was recorded during a 6-week period (baseline period). Then, during a period of 2 weeks (titration period), pregabalin was started with a dose of 25-75 mg/d, using method of flexible dose, and was brought to maximum dose of drug that was intended in this study (450 mg/d) based on clinical response of the patients and seizure frequency. Then the patients were given the drug for 12 weeks and the average frequency of daily and weekly seizures were recorded again (treatment period). Findings : Reduction in seizure frequency in this study was 36% and the responder rate or number of patients who gained more than 50% reduction in seizure frequency was 51.7%. CONCLUSION: This study showed that pregabalin can be used with safety and an acceptable efficacy in treatment of childhood refractory partial seizures.
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Proteínas de Membrana/genética , Síndrome Nefrótica/congênito , Linfoma de Burkitt/complicações , Cromossomos Humanos Par 19/genética , Consanguinidade , Éxons/genética , Evolução Fatal , Genótipo , Humanos , Lactente , Irã (Geográfico) , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Masculino , Síndrome Nefrótica/complicações , Síndrome Nefrótica/genética , Fenótipo , Sítios de Splice de RNA/genética , Splicing de RNA/genética , Análise de Sequência de DNARESUMO
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