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Stem and progenitor cells hold great promise for regenerative medicine and gene therapy approaches. However, transplantation of living cells entails a fundamental risk of unwanted growth, potentially exacerbated by CRISPR-Cas9 or other genetic manipulations. Here, we describe a safety system to control cell proliferation while allowing robust and efficient cell manufacture, without any added genetic elements. Inactivating TYMS, a key nucleotide metabolism enzyme, in several cell lines resulted in cells that proliferate only when supplemented with exogenous thymidine. Under supplementation, TYMS-/--pluripotent stem cells proliferate, produce teratomas, and successfully differentiate into potentially therapeutic cell types such as pancreatic ß cells. Our results suggest that supplementation with exogenous thymidine affects stem cell proliferation, but not the function of stem cell-derived cells. After differentiation, postmitotic cells do not require thymidine in vitro or in vivo, as shown by the production of functional human insulin in mice up to 5 months after implantation of stem cell-derived pancreatic tissue.
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Diferenciação Celular , Proliferação de Células , Timidina , Timidilato Sintase , Humanos , Animais , Camundongos , Timidina/metabolismo , Timidilato Sintase/genética , Timidilato Sintase/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Linhagem Celular , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/citologia , Sistemas CRISPR-CasRESUMO
Argininosuccinate lyase deficiency (ASLD) is a recessive metabolic disorder caused by variants in ASL. In an essential step in urea synthesis, ASL breaks down argininosuccinate (ASA), a pathognomonic ASLD biomarker. The severe disease forms lead to hyperammonemia, neurological injury, and even early death. The current treatments are unsatisfactory, involving a strict low-protein diet, arginine supplementation, nitrogen scavenging, and in some cases, liver transplantation. An unmet need exists for improved, efficient therapies. Here, we show the potential of a lipid nanoparticle-mediated CRISPR approach using adenine base editors (ABEs) for ASLD treatment. To model ASLD, we first generated human-induced pluripotent stem cells (hiPSCs) from biopsies of individuals homozygous for the Finnish founder variant (c.1153C>T [p.Arg385Cys]) and edited this variant using the ABE. We then differentiated the hiPSCs into hepatocyte-like cells that showed a 1,000-fold decrease in ASA levels compared to those of isogenic non-edited cells. Lastly, we tested three different FDA-approved lipid nanoparticle formulations to deliver the ABE-encoding RNA and the sgRNA targeting the ASL variant. This approach efficiently edited the ASL variant in fibroblasts with no apparent cell toxicity and minimal off-target effects. Further, the treatment resulted in a significant decrease in ASA, to levels of healthy donors, indicating restoration of the urea cycle. Our work describes a highly efficient approach to editing the disease-causing ASL variant and restoring the function of the urea cycle. This method relies on RNA delivered by lipid nanoparticles, which is compatible with clinical applications, improves its safety profile, and allows for scalable production.
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Argininossuccinato Liase , Acidúria Argininossuccínica , Humanos , Argininossuccinato Liase/genética , Acidúria Argininossuccínica/genética , Acidúria Argininossuccínica/terapia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , RNA Guia de Sistemas CRISPR-Cas , Ureia , Edição de Genes/métodosRESUMO
In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients' macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1ß secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-ß (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1ß and/or IFN-I signaling could represent a therapeutic approach for these patients.
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Fasciite Necrosante , Interferon Tipo I , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Imunidade Inata , Inflamação/metabolismo , Subunidade p50 de NF-kappa BRESUMO
Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.
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Alelos , DNA Polimerase gama , Vírus da Encefalite Transmitidos por Carrapatos , Herpesvirus Humano 1 , Tolerância Imunológica , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Camundongos , Idade de Início , COVID-19/imunologia , COVID-19/virologia , COVID-19/genética , DNA Polimerase gama/genética , DNA Polimerase gama/imunologia , DNA Polimerase gama/metabolismo , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Mutação , RNA Mitocondrial/imunologia , RNA Mitocondrial/metabolismo , SARS-CoV-2/imunologiaRESUMO
Introducción: La hipoxia intermitente consiste en la administración de aire reducido en oxígeno por episodios, para lograr hipoxia en sangre, alternados con intervalos de normoxia. Tiene uso terapéutico en varias patologías médicas, pero sus efectos psiquiátricos no han sido estudiados. Se han descrito efectos neurogénicos y en modelos animales puede ayudar a prevenir depresión y ansiedad en respuesta al estrés. Objetivo: Determinar la existencia de efectos psiquiátricos de la hipoxia normobárica intermitente en seres humanos. Método: Estudio prospectivo descriptivo. Se incluyeron pacientes mayores de 18 años, que tuvieran programado un plan de hipoxia normobárica intermitente en la clínica Hipoxykine. Se utilizó una ficha de registro y la escala breve de síntomas (BSI) que fue realizada al inicio, mitad (segunda semana) y finalizado el tratamiento (cuarta semana). Resultados: Se incluyeron 22 participantes (50% mujeres) con una mediana de edad de 46 años. Hubo una reducción del índice global de gravedad del BSI estadísticamente significativo (p <0.05) al comparar tanto la primera como la segunda medición respecto a la final. Respecto al análisis según género, esta diferencia fue estadísticamente significativa (p <0.05) en hombres. Conclusiones: La hipoxia normobárica intermitente no produce ni empeora síntomas psiquiátricos y podría tener potencial terapéutico. Se requieren nuevos estudios prospectivos.
Introduction: Intermittent normobaric hypoxia consists of the administration of air reduced in oxygen by episodes, to achieve hypoxia in blood alternated with intervals of normoxia. It has a role in brain development and neuroprotection. However, in the literature there are only studies in animal models. Objective: To determine the existence of psychiatric effects of intermittent normobaric hypoxia in humans. Method: Prospective descriptive study. We included patients over 18 years of age who had an intermittent normobaric hypoxia plan scheduled at the Hipoxykine clinic. A record sheet and the brief symptom inventory (BSI) were carried out at the beginning, middle (second week) and end of treatment (fourth week). Results: We included 22 participants (50% women) with a median age of 46 years. There was a reduction in the overall severity index of the statistically significant (p <0.05) when comparing both the first and second measurements with respect to the final. Regarding the analysis according to gender, this difference was statistically significant (p <0.05) in men. Conclusions: Intermittent normobaric hypoxia does not produce or worsen psychiatric symptoms. It could have therapeutic potential. Further prospective studies are required.
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Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) is a severe recessive inherited disease, causing muscular degeneration and retinochoroidal atrophy that progresses to blindness. HOGA arises from mutations in the ornithine aminotransferase (OAT) gene, and nearly one-third of the known patients worldwide are homozygous for the Finnish founder mutation OAT c.1205 T > C p.(Leu402Pro). We have corrected this loss-of-function OAT mutation in patient-derived induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. The correction restored OAT expression in stem cells and normalized the elevated ornithine levels in cell lysates and cell media. These results show an efficient recovery of OAT function in iPSC, encouraging the possibility of autologous cell therapy for the HOGA disease.
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BACKGROUND AND OBJECTIVES: Rather than focusing on the extensively studied social perception and recognition impairments in people with schizophrenia, this study focuses on the type of social information considered relevant by people with schizophrenia, and how they use it to arrive at conclusions about social situations. METHODS: Participants included 50 outpatients with schizophrenia from the Hospital del Salvador at Valparaíso, Chile, and 50 healthy comparators matched by age and gender. Subjects completed the Social Information Preference Test (SIPT), which presents scenes depicting ambiguous social situations with faces, thoughts, and facts about the scene hidden from view. Participants were required to select a limited number of these items and then choose between possible interpretations of the scene (positive, neutral, or negative). Additionally, they are asked to provide a feeling of certainty in their answers, using a 7-point visual analogue scale. RESULTS: People with schizophrenia, as well as controls had a strong preference for knowing the thoughts of the characters. Both groups were least likely to choose emotional expressions. Patients were significantly less likely to choose object/information than controls. Both groups showed a high certainty in their responses and no tendency to choose negative interpretations. LIMITATIONS: compensated clinical status of the patients may have influenced the results. CONCLUSIONS: The results of this study suggest that, despite difficulties perceiving clues about the mental state of others, people with schizophrenia use this information to make sense of social situations, and apparently, they do not have problems in understanding social interactions.
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Esquizofrenia , Emoções , Expressão Facial , Humanos , Percepção SocialRESUMO
ABSTRACT Background and objectives: Rather than focusing on the extensively studied social perception and recognition impairments in people with schizophrenia, this study focuses on the type of social information considered relevant by people with schizophrenia, and how they use it to arrive at conclusions about social situations. Methods: Participants included 50 outpatients with schizophrenia from the Hospital del Salvador at Valparaíso, Chile, and 50 healthy comparators matched by age and gender. Subjects completed the Social Information Preference Test (SIPT), which presents scenes depicting ambiguous social situations with faces, thoughts, and facts about the scene hidden from view. Participants were required to select a limited number of these items and then choose between possible interpretations of the scene (positive, neutral, or negative). Additionally, they are asked to provide a feeling of certainty in their answers, using a 7-point visual analogue scale. Results: People with schizophrenia, as well as controls had a strong preference for knowing the thoughts of the characters. Both groups were least likely to choose emotional expressions. Patients were significantly less likely to choose object/information than controls. Both groups showed a high certainty in their responses and no tendency to choose negative interpretations. Limitations: compensated clinical status of the patients may have influenced the results. Conclusions: The results of this study suggest that, despite difficulties perceiving clues about the mental state of others, people with schizophrenia use this information to make sense of social situations, and apparently, they do not have problems in understanding social interactions.
RESUMEN Objetivos: En lugar de los impedimentos en la percepción social, ampliamente estudiada en personas con esquizofrenia, centramos nuestra investigación en el tipo de información social considerada relevante por las personas con esquizofrenia y cómo la usan para llegar a conclusiones sobre situaciones sociales. Métodos: Se incluyó a 50 pacientes ambulatorios con esquizofrenia del Hospital del Salvador en Valparaíso, Chile, y 50 comparadores sanos, emparejados por edad y sexo. Los sujetos completaron la Prueba de Preferencia de Información Social (SIPT), que presenta escenas con situaciones sociales ambiguas en las que rostros, pensamientos y hechos sobre la escena están ocultos a la vista. Los participantes deben seleccionar un pequeño número de estos elementos y luego elegir entre posibles interpretaciones (positiva, neutral o negativa). Además, se les pide que proporcionen una sensación de certeza en sus respuestas, utilizando una escala analógica visual de 7 puntos. Resultados: Tanto las personas con esquizofrenia como los comparadores mostraron una fuerte preferencia por conocer los pensamientos de los personajes. La opción menos preferida por ambos grupos fue las expresiones emocionales, mientras que los pacientes escogieron menos objeto/información que los controles. Ambos grupos mostraron una alta certeza en sus respuestas y no se observó una tendencia a elegir interpretaciones negativas. Limitaciones: el estado clínico compensado de los pacientes puede haber influido en los resultados. Conclusiones: Los resultados de este estudio indican que, a pesar de las dificultades para percibir pistas sobre el estado mental de los demás, las personas con esquizofrenia usan esta información para dar sentido a las situaciones sociales y, aparentemente, no presentan problemas para comprender las interacciones sociales.
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BACKGROUND AND OBJECTIVES: The tendency of people with schizophrenia to gather insufficient information before making decisions or jumping to conclusions has been repeatedly reported. However, criticism has also been expressed regarding the ecological validity of this finding. Here we present the results obtained by a group of people with schizophrenia and a control group in a non-probabilistic task that requires obtaining items of information before interpreting an ambiguous social situation. METHODS: Patients with schizophrenia (n = 48) and controls (n = 44) aged 18-50 years participated in the study. All subjects completed the Beads Task and the modified Social Information Preference Task. RESULTS: Patients with schizophrenia showed a statistically significant tendency to jump to conclusions, including in the proposed novel social task. Unlike other studies, we were unable to find a relationship between this bias and greater severity of psychotic symptoms. LIMITATIONS: We did not include patients with high levels of psychotic symptoms or a clinical control group. CONCLUSIONS: The tendency to jump to conclusions in schizophrenia could be present in everyday interpersonal situations.
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Transtornos Psicóticos , Esquizofrenia , Adolescente , Adulto , Tomada de Decisões , Delusões , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Human induced pluripotent stem cells (hiPSCs) allow in vitro study of genetic diseases and hold potential for personalized stem cell therapy. Gene editing, precisely modifying specifically targeted loci, represents a valuable tool for different hiPSC applications. This is especially useful in monogenic diseases to dissect the function of unknown mutations or to create genetically corrected, patient-derived hiPSCs. Here we describe a highly efficient method for simultaneous base editing and reprogramming of fibroblasts employing a CRISPR-Cas9 adenine base editor. As a proof of concept, we apply this approach to generate gene-edited hiPSCs from skin biopsies of four patients carrying a Finnish-founder pathogenic point mutation in either NOTCH3 or LDLR genes. We also show LDLR activity restoration after the gene correction. Overall, this method yields tens of gene-edited hiPSC monoclonal lines with unprecedented efficiency and robustness while considerably reducing the cell culture time and thus the risk for in vitro alterations.
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Reprogramação Celular/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Edição de Genes , Sequência de Bases , Células Cultivadas , Endoderma/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Fenótipo , RNA/genética , Receptor Notch3/genética , Receptores de LDL/genética , TransgenesRESUMO
Basic emotions are universally recognized, although diï¬erences across cultures and between genders have been described. We report results in two emotion recognition tasks, in a sample of healthy adults from Chile. METHODS: 192 volunteers (mean 31.58 years, s.d. 8.36; 106 women) completed the Emotional Recognition Task, in which they were asked to identify a brieï¬y displayed emotion, and the Emotional Intensity Morphing Task, in which they viewed faces with increasing or decreasing emotional intensity and indicated when they either detected or no longer detected the emotion. RESULTS: All emotions were recognized at above chance levels. The only sex diï¬erences present showed men performed better at identifying anger (p = .0485), and responded more slowly to fear (p = .0057), than women. DISCUSSION: These ï¬ndings are consistent with some, though not all, prior literature on emotion perception. Crucially, we report data on emotional perception in a healthy adult Latino population for the ï¬rst time, which contributes to emerging literature on cultural diï¬erences in aï¬ective processing.
Las emociones básicas son reconocidas universalmente, aunque se han descrito diferencias entre culturas y géneros. Reportamos resultados en dos tareas de reconocimiento de emociones, en una muestra de adultos sanos de Chile. Métodos: 192 voluntarios (31.58 años, d.e. 8.36; 106 mujeres) completaron la Emotional Recognition Task, en la que se pidió identiï¬car una emoción exhibida brevemente, y la Emotional Intensity Morphing Task, en la que vieron caras con aumento o disminución de la intensidad emocional e indicando cuando detectaron o dejaron de detectar la emoción. Resultados: Todas las emociones fueron reconocidas en niveles superiores al azar. Las únicas diferencias por género, estadísticamente signiï¬cativas, se encontraron en los hombres, identiï¬cando mejor el enojo (p = .0485) y reaccionando más lentamente al miedo (p = .0057). Discusión: nuestro estudio, además de conï¬rmar hallazgos previos y discrepar con otros, agrega datos previamente inexistentes sobre la percepción emocional en una población latina adulta saludable.
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Diseases caused by alterations in the DNA can be overcome by providing the cells or tissues with a functional copy of the mutated gene. The most common form of gene therapy implies adding an extra genetic unit into the cell. However, new genome engineering techniques also allow the modification or correction of the existing allele, providing new possibilities, especially for dominant diseases. Gene therapies have been tested for 30 years in thousands of clinical trials, but presently, we have only three authorised gene therapy products for the treatment of inherited diseases in European Union. Here, we describe the gene therapy alternatives already on the market in the European Union and expand the scope to some clinical trials. Additionally, we discuss the ethical and regulatory issues raised by the development of these new kinds of therapies.
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BACKGROUND AND OBJECTIVES: Rather than focusing on the extensively studied social perception and recognition impairments in people with schizophrenia, this study focuses on the type of social information considered relevant by people with schizophrenia, and how they use it to arrive at conclusions about social situations. METHODS: Participants included 50 outpatients with schizophrenia from the Hospital del Salvador at Valparaíso, Chile, and 50 healthy comparators matched by age and gender. Subjects completed the Social Information Preference Test (SIPT), which presents scenes depicting ambiguous social situations with faces, thoughts, and facts about the scene hidden from view. Participants were required to select a limited number of these items and then choose between possible interpretations of the scene (positive, neutral, or negative). Additionally, they are asked to provide a feeling of certainty in their answers, using a 7-point visual analogue scale. RESULTS: People with schizophrenia, as well as controls had a strong preference for knowing the thoughts of the characters. Both groups were least likely to choose emotional expressions. Patients were significantly less likely to choose object/information than controls. Both groups showed a high certainty in their responses and no tendency to choose negative interpretations. LIMITATIONS: compensated clinical status of the patients may have influenced the results. CONCLUSIONS: The results of this study suggest that, despite difficulties perceiving clues about the mental state of others, people with schizophrenia use this information to make sense of social situations, and apparently, they do not have problems in understanding social interactions.
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Alterations in neuroinflammatory processes have been suggested to contribute to the development of Schizophrenia (SZ); one component of the inflammatory system that has been linked to this disorder is interleukin-6 (IL-6). The minor allele of rs2228145, a functional polymorphism in the IL-6 receptor gene, has been associated to elevated IL-6 plasma levels and increased inflammatory activity, making it an interesting candidate to study as a possible factor underlying clinical heterogeneity in SZ. We studied a sample of 100 patients undergoing treatment with clozapine. Their symptoms were quantified by Brief Psychotic Rating Scale; those with the lowest scores ("remitted") were compared with the highest ("clozapine treatment resistant"). We determined allelic frequencies for rs2228145 and IL-6 plasma levels. Our results do not support a role of IL-6 in response to treatment with clozapine. Further studies accounting for potential confounding factors are necessary.
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BACKGROUND: Musculoskeletal Ultrasonography (MSUS) is an important tool for the clinical assessment in Juvenile Idiopathic Arthritis (JIA). The objective of this study was to evaluate the reliability of MSUS to detect elementary lesions: synovitis, tenosynovitis, cartilage damage and bone erosions in the wrist and metacarpal (MCP) joints of patients with JIA. METHODS: Thirty children in various subgroups of JIA according to ILAR criteria, were included in this cross-sectional study. Clinical data including painful, swollen and limited joints were recorded. Five rheumatologist ultrasonographers, blinded to the clinical evaluation, evaluated the presence of elementary lesions in the wrist and MCP 2 and 3 joints bilaterally. The synovitis was graded in B-Mode and Power Doppler (PD). In addition to descriptive statistics intra- and inter-observer reliability was calculated using Cohen's kappa according to Landis and Koch. RESULTS: US detected more synovitis than the clinical examination (62% vs 28%, 30% vs 23% and 22% vs 17% in the wrist, second and third MCP joints respectively). The intra-observer concordance for synovitis in all joints was excellent in B-Mode (k 0.84 .63-1.0 p = 0.001), except for MCP 2, where it was good (0.61, IC 95% .34-89, p = 0.001). For both modalities (PD, B-Mode) tenosynovitis, cartilage damage and bone erosions it was also excellent. Regarding synovitis grading the concordance was excellent for all grades (0.83-1.0, IC 95% 0.51.1.0, p = 0.001), except for grade 1 where it was good (0.61, IC 95% 0.43-.83, p = 0.001). Reliability inter-observer for grayscale synovitis (0.67-0.95, IC 95% 0.67-1.0, p = 0.001), tenosynovitis grayscale (0.89, IC 95% 0.78-0.99, p.001), damage cartilage (0.89, IC 95% 0.78-0.99, p = 0.001), PD (0.66, IC 95% 0.39-1.0, p = 0.001). The concordance for grading synovitis was excellent, but for grayscale grade 1 and 2 (.66, IC 95% .53-.74, p = 0.007) and PD grade 1 and 2 (0.63, IC 95% .58-.91, p = 004) was good. CONCLUSIONS: The intra- and inter-observer reliability of MSUS for inflammatory and structural lesions is good to excellent for the wrist and MCP in patients with JIA.
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Artrite Juvenil/diagnóstico por imagem , Articulação Metacarpofalângica/diagnóstico por imagem , Ultrassonografia/métodos , Articulação do Punho/diagnóstico por imagem , Artrite Juvenil/patologia , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Articulação Metacarpofalângica/patologia , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Articulação do Punho/patologiaRESUMO
BACKGROUND: Monocyte chemotactic protein-1 (MCP-1) plays a direct role in the infiltration of macrophages and monocytes during the early stages of Henoch-Schönlein purpura (HSP) nephritis. The aim of this study was to compare the urinary MCP-1/creatinine levels in children with and without HSP nephritis and determine if they are associated with the severity of renal lesions. METHODS: We included 77 patients with HSP and 25 healthy control children. Levels of serum creatinine, urinalysis, and 12-h proteinuria assessments were performed. Urinary MCP-1 levels were determined by ELISA. RESULTS: Fifty-seven patients had nephritis (74 %). Urinary MCP-1/creatinine levels were significantly higher in patients with HSP nephritis (median, 653 pg/mg) compared to those with HSP without nephritis (median, 269 pg/mg) or healthy children (191 pg/mg). In addition, higher MCP-1/creatinine levels were observed in HSP patients who had renal biopsy (median, 1,412 pg/mg) in comparison to HSP patients without renal biopsy (median, 302 pg/mg). The urinary MCP-1 cut-off value of 530 pg/mg could be used to distinguish patients who undergo renal biopsy with a sensitivity of 81 % and specificity of 77 %. CONCLUSIONS: Urinary MCP-1/creatinine levels are elevated in the early stages of severe HSP nephritis and can be used as a biomarker for HSP nephritis.
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Quimiocina CCL2/urina , Creatinina/urina , Vasculite por IgA/complicações , Vasculite por IgA/urina , Nefrite/urina , Adolescente , Área Sob a Curva , Biomarcadores/urina , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Vasculite por IgA/patologia , Lactente , Masculino , Nefrite/etiologia , Nefrite/patologia , Curva ROCRESUMO
Introducción. La hemangiomatosis neonatal difusa es una entidad poco frecuente. Es un trastorno grave en el que aparecen múltiples hemangiomas cutáneos y viscerales de distribución amplia y, en ocasiones, puede ser fatal. Las complicaciones incluyen falla cardiaca, hemorragias, falla hepática, entre otras. El tratamiento está encaminado a evitar los efectos adversos y las complicaciones. Caso clínico. Se trata de un paciente masculino de 53 días de vida que acudió al hospital por presentar lesiones cutáneas y sangrado de tubo digestivo alto. Durante su internamiento se encontraron hemangiomas viscerales en pulmón, bazo y mucosa gástrica. Recibió tratamiento con interferón alfa-2b y corticosteroides. Los hemangiomas de mucosa gástrica fueron coagulados con argón plasma. Conclusiones. La hemangiomatosis neonatal diseminada es una entidad rara que puede ser mortal si no recibe tratamiento. El paciente evolucionó satisfactoriamente y actualmente se encuentra asintomático.
Introduction. Diffuse neonatal hemangiomatosis is a rare entity and is a serious disorder in which multiple cutaneous and visceral hemangiomas are widely distributed and sometimes may be fatal. Complications include heart failure, bleeding, and liver failure, among others. Treatment is aimed at avoiding adverse effects and complications. Case report. We report the case of a 53-day-old male patient who presented to the hospital for skin lesions and upper gastrointestinal bleeding. During his hospital stay, visceral hemangiomas were found in the lung, spleen and gastric mucosa. He was treated with interferon alpha-2b corticosteroids and hemangiomas of gastric mucosa were treated with argon plasma coagulation. Conclusions. Disseminated neonatal hemangiomatosis is a rare entity and can be fatal if untreated. Our patient experienced a satisfactory evolution and is currently asymptomatic.
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Introducción. La púrpura de Henoch-Schönlein (PHS) es la vasculitis más frecuente en niños. Objetivo: conocer la presentación clínica y evolución de los pacientes con PHS que se han tratado en el hospital en los últimos 5 años. Material y métodos. Estudio retrospectivo en pacientes que acudieron al Hospital Infantil de México Federico Gómez, del 1 de enero de 2000 al 31 de diciembre de 2005, con diagnóstico de PHS. Resultados. Se encontraron 105 pacientes con una mediana de edad de 6 años. El tiempo promedio de seguimiento fue de 15 meses. Todos presentaron lesiones dérmicas, 49.5% dolor abdominal y 41% artritis; 45 (42.9%) pacientes manifestaron nefropatía, con un promedio de aparición de 4.5 meses después de las lesiones dérmicas. Sólo en 37.7% de los casos con nefropatía desaparecieron las alteraciones urinarias. Se realizó biopsia renal en 14 pacientes. La lesión histopatológica más frecuente fue el grado IIIA. La edad de presentación tuvo relación estadísticamente significativa con la presencia de nefritis, los mayores de 10 años tuvieron mayor incidencia de nefritis y los menores de 5 años menor incidencia (Chi cuadrada, P < 0.05). La incidencia global de insuficiencia renal crónica fue de 0.95%. Conclusión. La edad de presentación es un factor pronóstico para la evolución de la enfermedad. Si bien la púrpura es una vasculitis, la principal complicación a largo plazo es renal, por lo que el seguimiento de los pacientes debe ser supervisado por un nefrólogo pediatra.
Introduction. Henoch-Schönlein purpura (HSP) is the most frequent vasculitis in children. Objective: To describe the clinical presentation and clinical outcome in children with HSP treated in our hospital in the last 5 years. Material and methods. A retrospective study was performed in HSP patients diagnosed between January 1st 2001 and December 31st 2005. Results. HSP was diagnosed in 105 patients, median age 6 years old. All had the skin manifestations, 49.5% abdominal pain and 41% arthritis; 45 patients developed HSP nephritis (42.9%), mean presentation time was 4.5 months after HSP diagnosis. Renal biopsy was performed in 14 patients, and the most common histopathological finding was HSP nephritis grade III A. Age of onset older than 10 years was statistically significant for nephritis development (Chi Square < 0.05). Chronic renal insufficiency incidence was 0.95%. Conclusions. The main complication of HSP is nephritis. Follow-up should include evaluation by a pediatric nephrologist. Age of onset older than 10 years is an important risk factor for HSP nephritis.
RESUMO
Dental fluorosis is an endemic dental health problem around the world; so, it is important to develop clinical alternatives that are non-invasive and inexpensive. In this study, nightguard vital bleaching technique (NVBT), using carbamide and hydrogen peroxide as active agents, has shown itself to be effective in whitening teeth affected by dental fluorosis. Carbamide peroxide at 10 and 20% and hydrogen peroxide at 7.5% showed good clinical effectiveness in improving clinical appearence, but it is important to point out that clinical success is only in cases of class 1 to 3 of the Tooth Surface Index of Fluorosis. When comparing 10 and 20% concentrations of carbamide peroxide, there was no difference in the clinical effectiveness (p > 0.05); but when comparing both concentrations of carbamide peroxide against hydrogen peroxide, results showed that carbamide peroxide was more effective in whitening in cases of dental fluorosis, the difference being statistically significant (p < 0.05). NVBT has two advantages: it is a non-invasive technique and the relationship cost/benefit is excellent; only a few patients reported tenderness or mild tooth sensitivity.
Assuntos
Fluorose Dentária/reabilitação , Clareamento Dental/métodos , Descoloração de Dente/tratamento farmacológico , Ureia/análogos & derivados , Adolescente , Adulto , Peróxido de Carbamida , Dispositivos para o Cuidado Bucal Domiciliar , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Fluorose Dentária/complicações , Humanos , Peróxido de Hidrogênio/administração & dosagem , Masculino , Oxidantes/administração & dosagem , Peróxidos/administração & dosagem , Estatísticas não Paramétricas , Descoloração de Dente/etiologia , Ureia/administração & dosagemRESUMO
La leishmaniasis cutanea (LC) es una zoonosis que representa un problema de salud publica en el Ecuador, al igual que en la mayoría de países latinoamericanos. Sin embargo, existe poca información sobre los conocimientos etnomedicos y prácticas terapéuticas en esta enfermedad. Se realizaron dos estudios en los que se investigó el uso de los tratamientos para la LC en una área endémica de Ecuador. alrededor del 80 por ciento de los adultos mencionaron al menos un tipo de tratamiento tradicional o convencional para la LC. De los 175+ métodos terapéuticos especificados, una tercera parte correspondió al uso tópico de hierbas, leche o resina de árboles, frutas, u otras plantas autoctonas. Los otros métodos incluyen antibióticos, varios ácidos, productos químicos, polvos, pomadas, lacas, productos derivados del petróleo, agua u objetos calientes y varios productos animales. Menos del 25 por ciento mencionó al Glucantimer, el tratamiento convencional que se usa actualmente en LC. La mayoría de estos métodos son probablemente inocuos; sin embargo, algunos de ellos como ácidos, agentes cáusticos y metales calientes incrementan la lesión y dan como resultado cicatrices más grandes y profundas en relación a la que causa la ulcera de la LC. En forma adicional, la aplicación de sustancias como el cloro, gasolina, mercurio y plomo en las úlceras abiertas pueden ser carciongénicas o causar defectos en los fetos de mujeres em barazadas. Es importante considerar que varios de estos métodos tradicionales pueden tener valor terapéutico, entre los que se pueden mencionar el agua caliente y las plantas que contienen alcaloides, terpenos y otros componenetes naturales con actividad antiprotozoaria; por consiguiente, su valor potencial debe ser investigado como alternativas terapéuticas en la LC.