RESUMEN
Overexpression of the TGFß pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFß promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFß signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFß pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFß and NHEJ pathway genes are overexpressed during the embryogenesis of Fancd2-/- mice and that the Fancd2-/-Smad3-/- double knockout (DKO) mice undergo high levels of embryonic lethality due to loss of the TGFß-NHEJ axis. Fancd2-deficient embryos acquire extensive genomic instability during gestation which is not reversed by Smad3 inactivation. Strikingly, the few DKO survivors have activated the non-canonical TGFß-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFß-NHEJ axis was critical for the survival of the few Fancd2-/-Smad3-/- DKO newborn mice but had detrimental consequences for these surviving mice, such as enhanced genomic instability and ineffective hematopoiesis.
Asunto(s)
Anemia de Fanconi , Ratones , Animales , Anemia de Fanconi/genética , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Early life stress increases the risk of developing psychiatric diseases in adulthood. Severe neonatal infections can also contribute to the development of affective illnesses. Stress and infections both trigger the immediate activation of the neuroimmune system. We compared the long-term effects of neonatal single or combined stress-immune challenges on emotional behavior and glial cell responses in the hippocampus. Male and female Sprague Dawley rats were randomly allocated across four conditions: (1) control + vehicle; (2) maternal separation (MS, 3 h/day on postnatal days [PN] 1-14) + vehicle; (3) control + lipopolysaccharide (LPS, 0.5. mg/kg, PN14); (4) MS + LPS. The rats' behaviors were analyzed from PN120 in males and from PN150 in diestrous females. LPS, but not MS, increased anxiety-like behavior in male rats; however, in females, it increased with both challenges. Depressive-like behavior increased after MS-but not LPS-in males and females. Combined stressors increased depressive-like behavior in both sexes. All stressors promoted microglial activation in CA3 and hilus in males and females. MS and LPS increased the astrocytic density within the male hilus, but LPS only increased it in CA3. MS prevented the rise in astrocytic density with LPS. In females, MS reduced the astrocytic population of the hilus and CA3 areas. Taken together, the behavioral and glial cell responses to early life challenges are sex-dependent and cell-type specific. This suggests a sexual dimorphism in the nature of the adverse event faced. These results have implications for understanding the emergence of psychiatric illnesses.
Asunto(s)
Conducta Animal , Emociones , Hipocampo , Neuroglía , Estrés Psicológico , Animales , Animales Recién Nacidos , Conducta Animal/fisiología , Emociones/fisiología , Femenino , Hipocampo/metabolismo , Lipopolisacáridos/metabolismo , Masculino , Privación Materna , Neuroglía/metabolismo , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor ß (TGFß) pathway, regulated by the TGFß1, TGFß2, and TGFß3 ligands. Accordingly, the TGFß pathway is an attractive therapeutic target for FA. While inhibition of TGFß1 and TGFß3 promotes blood cell expansion, inhibition of TGFß2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGFß1- and TGFß3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA.
Asunto(s)
Anemia de Fanconi/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta3/antagonistas & inhibidores , Adolescente , Adulto , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Niño , Preescolar , Anemia de Fanconi/metabolismo , Anemia de Fanconi/fisiopatología , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Masculino , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta3/metabolismoRESUMEN
Bone marrow failure (BMF) in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGF-ß pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow.
Asunto(s)
Anemia de Fanconi , Animales , Médula Ósea , Daño del ADN , Anemia de Fanconi/genética , Células Madre Hematopoyéticas , Humanos , Ratones , Factor de Crecimiento Transformador betaRESUMEN
Introducción: Los tumores suprarrenales en niños son poco frecuentes y el carcinoma suprarrenal representa menos de un 10 %. En el prepúber, la manifestación más típica es el desarrollo de pubertad precoz. Objetivo: Describir las características clínicas, los procederes diagnósticos y terapéuticos de un paciente con carcinoma adrenal en edad pediátrica. Presentación de caso: Paciente de 8 años, masculino y de piel blanca con antecedentes de salud. Acude a la consulta por crecimiento de vello pubiano y aumento del pene en longitud y grosor de aproximadamente 2 años de evolución. En el examen físico se constatan aumento de la velocidad de crecimiento y signos sugestivos de virilización (voz gruesa, vello axilar, vello sexual púbico y genitales externos estadio III de Tanner). Se realizaron estudios hormonales que corroboraron el hiperandrogenismo por secreción endógena autónoma, con niveles de gonadotropinas suprimidas, niveles de testosterona y dehidroepiandrosterona elevados. También se realizaron estudios imagenológicos que evidenciaron edad ósea acelerada y la existencia de un tumor. Se realizó una adrenalectomía izquierda y se confirmó por anatomía patológica el carcinoma corticosuprarrenal virilizante izquierdo en estadío 2. Inició un tratamiento con quimioterapia por dicho diagnóstico y actualmente se mantiene en seguimiento. Conclusiones: Los carcinomas corticosuprarrenales en niños son mayoritariamente funcionantes y constituyen una de las causas de pubertad precoz periférica. Estos son infrecuentes y agresivos, por lo que la realización de estudios genéticos en familias con síndromes hereditarios contribuiría a su diagnóstico precoz para un adecuado tratamiento y mejor pronóstico(AU)
Introduction: Adrenal tumors in children are rare and adrenal carcinoma represents less than the 10 percent. In the prepubescent, the most typical manifestation is the development of early puberty. Objective: Describe the clinical characteristics and diagnostic and therapeutic procedures of a patient with adrenal carcinoma in a pediatric age. Case presentation: 8-year-old male, white-skinned patient with a history of health conditions. He attentds to the consultation due to pubic hair growth and penis enlargement in length and thickness of approximately 2 years of evolution. Physical examination shows increased growth rate and signs suggestive to virilization (deep voice, axillary hair, pubic sexual hair and external genitalia in Tanner's stage III). Hormonal studies were carried out that corroborated hyperandrogenism by autonomic endogenous secretion, with suppressed gonadotropin levels, elevated testosterone and dehydroepiandrosterone levels. Imaging studies were also performed that showed accelerated bone age and the existence of a tumor. A left adrenalectomy was performed and stage 2 left virilizing adrenocrotical carcinoma was confirmed by pathological anatomy studies. He began chemotherapy treatment for this diagnosis and is currently being followed up. Conclusions: Adrenocortical carcinomas in children are mostly functioning and are one of the causes of peripheral early puberty. These are uncommon and aggressive, so genetic studies in families with hereditary syndromes would contribute to their early diagnosis for adequate treatment and better prognosis(AU)
Asunto(s)
Humanos , Masculino , Niño , Hiperandrogenismo , Carcinoma Corticosuprarrenal/diagnóstico , Pubertad Precoz , Virilismo , Diagnóstico PrecozRESUMEN
BACKGROUND: Urinary tract infection is one of the most common infections at all ages. Antimicrobial resistance has increased in the past few years. The aim of this study was to determine the most common etiologic agents of urinary tract infections and their antimicrobial susceptibility profiles. METHODS: A descriptive, cross-sectional survey was conducted. Patients with a urinary tract infection identified over a 1-year period were included. The type of infection, risk condition, antimicrobial treatment, microorganism and antimicrobial susceptibility were recorded. STATISTICAL ANALYSIS: descriptive statistics. RESULTS: One hundred and seventy four patients with infection, 31.4 % with urinary tract malformation, 56 % with functional abnormalities. 76.4 % were receiving antimicrobial prophylaxis. Escherichia coli was the most common agent isolated with 67%, followed by Klebsiella spp. 9 %, Pseudomonas spp. 7 % and others less frequently. Escherichia coli resistance to cephalotin was 58.7%, to norfloxacin 51 %, nitrofurantoin 15.5 %, cefuroxime 12.5 %, cefotaxime 15.5 %, cefepime 5 % and to amikacin 0 %. CONCLUSIONS: Escherichia coli was the most common causative agent, and resistance to quinolones and cephalotin was higher than 50 %. Most patients had urinary tract functional abnormalities and a history of prophylactic treatment use. Options other than quinolones need to be assessed due to the high resistance identified in uropathogens.
INTRODUCCIÓN: la infección urinaria es una de las más comunes en todas las edades. Recientemente se ha incrementado la resistencia antimicrobiana. El objetivo del estudio fue determinar los agentes etiológicos más frecuentes de infección urinaria y sus perfiles de susceptibilidad antimicrobiana. MÉTODOS: se llevó a cabo una encuesta transversal descriptiva. Se incluyeron los pacientes con infección urinaria identificados durante un año. Se registró tipo de infección, condición de riesgo, tratamientos antimicrobianos, microorganismos y resistencia antimicrobiana. El análisis de los datos se llevó a cabo mediante estadística descriptiva. RESULTADOS: se identificaron 174 pacientes con infección, 31.4 % con malformación del tracto urinario y 56 % con alteraciones funcionales; 76.4 % recibía profilaxis antimicrobiana. Escherichia coli fue el agente más frecuente (67 %), seguido de Klebsiella spp. (9 %) y Pseudomonas spp. (7 %). Se observó resistencia de Escherichia coli a cefalotina (58.7 %), norfloxacina (51 %), nitrofurantoína (15.5 %), cefuroxima (12.5 %), cefotaxima (15.5 %) y cefepime (5 %). CONCLUSIONES: Escherichia coli fue el agente causal más frecuente y la resistencia a quinolonas y cefalotina fue superior a 50 %. La mayoría de los pacientes tenían alteraciones funcionales de la vía urinaria y antecedente de uso de tratamiento profiláctico. Es necesario evaluar opciones diferentes a las quinolonas, dada la elevada resistencia que se identificó en los uropatógenos.
Asunto(s)
Farmacorresistencia Bacteriana , Infecciones Urinarias/microbiología , Adolescente , Antibacterianos/farmacología , Antiinfecciosos , Niño , Preescolar , Estudios Transversales , Escherichia coli/efectos de los fármacos , Femenino , Hospitales Pediátricos , Humanos , Lactante , Masculino , Pruebas de Sensibilidad MicrobianaRESUMEN
Routine karyotyping of an eleven-year-old female being investigated for proportional short stature revealed a 44, X, der(15; 22)(q10;q10) karyotype. This is the first case report of a patient with monosomy X and an aparently balanced 15:22 translocation(AU)
El cariotipo de rutina de un individuo del sexo femenino de once años de edad, que estaba siendo estudiado por una baja talla proporcionada, reveló el siguiente resultado: 44, X, der(15; 22)(q10;q10). En este trabajo se reporta el hallazgo cromosómico en el que se combina una monosomía del X y una translocación 15:22 aparentemente balanceada(AU)
Asunto(s)
Humanos , Femenino , Translocación Genética , Síndrome de TurnerRESUMEN
Se presentan tres niños tratados por los Servicios de Endocrinología y Urología del Hospital Pediátrico Octavio de la Concepción y de la Pedraja de Holguín, en el período entre 1999 y 2003 a los cuales se les diagnosticó pseudopubertad precoz producido por tumores de las células intersticiales de Leydig. Se sometieron a tratamiento quirúrgico para realizarles orquiectomía inguinal del testículo afectado, con lo cual se obtuvo detención del crecimiento genital y reversión parcial de la virilización. La evolución postoperatoria de los pacientes fue satisfactoria...(AU)
Three children that were assisted at Pediatric Hospital , Endocrinology and Urology Service in Holguin between 1999 and 2003 year were diagnosed with precocious pseudopuberty caused by Leydig interstitial cells tumors. Surgical treatment was given. Inguinal orchiectomy of the affected testis was done which stopped genital growth and partial reversion of virilization. Postoperative evolution was satisfactory...(AU)
Asunto(s)
Niño , Orquiectomía , Tumor de Células de Leydig/diagnóstico , Pubertad PrecozRESUMEN
El síndrome de Cushing es la expresión clínica de un hipercorticismo crónico de etiología endógena o exógena. En el niño la causa más frecuente de este padecimiento es la administración de glucocorticoides especialmente fluorados utilizados en una amplia gama de enfermedades: reumáticas, dermatológicas, endocrinas, etcétera. En las enfermedades dermatológicas con componente inflamatorio, su uso tópico ofrece excelentes resultados pero no está exento de reacciones adversas. Fue nuestro propósito la presentación de tres pacientes atendidos en el Hospital Octavio de la Concepción y de la Pedraja afectados por esta complicación...(AU)
Cushing's Syndrome is the clinical manifestation of a chronic hypercorticalism of endogenous or exogenous etiology. The most frequent cause of Cushing's Syndrome in children is the administration of glucocorticoids, specially flurides,used in an broad spectrum of rheumatic, dermatological, endocrine disease and others. In dermatological diseases with inflammatory components its topical use offers excellent results, but it might cause adverse reactions . The purpose of this work is to present three patients that were assisted at Octavio de la Concepcion y de la Pedraja Hospital suffering from this complication...(AU)
Asunto(s)
Niño , Síndrome de Cushing , CorticoesteroidesAsunto(s)
Humanos , Niño , Pediatría , Anestesia , Procedimientos Quirúrgicos Otorrinolaringológicos , Otolaringología , AnestesiologíaRESUMEN
As doenças crônicas, como a Diabetes Mellitus, é um dos agravos à saúde mais comuns, que mais demandam por ações de educação em saúde, pois somente o autocontrole dos níveis de glicose, prática de atividade física e dieta alimentar, são instrumentos fundamentais para o seu controle. Neste estudo, objetiva interferir de maneira positiva na linha de controle metabólico as pessoas com diagnóstico de Diabetes Mellitus, através da educação sanitária oferecida por meio de oficinas educativas, utilizando metodologia participativa e técnicas lúdicas, envolvendo a participação de 50 usuários com diabetes na Unidade Básica de Saúde Ipuca, no município São Fidelis. A metodologia participativa valorizou o conhecimento prévio dos participantes em relação à fisiopatologia, dieta e atividade física e responsabilidade frente ao autocuidado. A oficina mostrou-se como espaço de reflexão e debate sobre a adoção de hábitos saudáveis, concluiu-se que os programas de educação em diabetes permite a vivência e a experiência em se trabalhar de forma conjunta, integrando e compartilhando conhecimentos, visando a redução da mortalidade por esta doença e pra melhorar a qualidade de vida e o melhor cuidado do usuário e da comunidade.