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2.
Chest ; 160(4): 1350-1359, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34089740

RESUMO

BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.


Assuntos
Deficiência de GATA2/fisiopatologia , Nódulos Pulmonares Múltiplos/fisiopatologia , Proteinose Alveolar Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/fisiopatologia , Enfisema Pulmonar/fisiopatologia , Infecções Respiratórias/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Deficiência de GATA2/diagnóstico por imagem , Deficiência de GATA2/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Infecções por Mycobacterium não Tuberculosas/fisiopatologia , Enfisema Pulmonar/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto Jovem
3.
J Clin Immunol ; 37(6): 592-602, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28755066

RESUMO

PURPOSE: Common variable immunodeficiency (CVID) is a complex, heterogeneous immunodeficiency characterized by hypogammaglobulinemia, recurrent infections, and poor antibody response to vaccination. While antibiotics and immunoglobulin prophylaxis have significantly reduced infectious complications, non-infectious complications of autoimmunity, inflammatory lung disease, enteropathy, and malignancy remain of great concern. Previous studies have suggested that CVID patients diagnosed in childhood are more severely affected by these complications than adults diagnosed later in life. We sought to discern whether the rates of various infectious and non-infectious conditions differed between pediatric-diagnosed (ages 17 or younger) versus adult-diagnosed CVID (ages 18 or older). METHODS: Using the United States Immunodeficiency Network (USIDNET) database, we performed a retrospective analysis of 457 children and adults with CVID, stratified by age at diagnosis. Chi-squared testing was used to compare pediatric versus adult groups. RESULTS: After correcting for multiple comparisons, we identified few statistically significant differences (p ≤ 0.0004) between pediatric and adult groups. Pediatric-onset CVID patients had more frequent diagnoses of otitis media, developmental delay, and failure to thrive compared with adult-onset CVID patients. Adult CVID patients were more frequently diagnosed with bronchitis, arthritis, depression, and fatigue. Diagnoses of autoimmunity, lymphoma, and other malignancies were higher in adults but not to a significant degree. Serum immunoglobulins (IgG, IgA, and IgM) and lymphocyte subsets did not differ significantly between the two groups. When complications of infections and co-morbid conditions were viewed categorically, there were few differences between pediatric-onset and adult-onset CVID patients. CONCLUSIONS: These results suggest that pediatric CVID is not a distinct phenotype. Major features were comparable across the groups. This study underscores the need for continued longitudinal study of pediatric and early-onset CVID patients to further characterize accrual of features over time.


Assuntos
Artrite/fisiopatologia , Bronquite/fisiopatologia , Imunodeficiência de Variável Comum/fisiopatologia , Depressão/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Insuficiência de Crescimento/fisiopatologia , Otite Média/fisiopatologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Artrite/epidemiologia , Autoimunidade , Bronquite/epidemiologia , Transformação Celular Neoplásica , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/epidemiologia , Bases de Dados Factuais , Depressão/epidemiologia , Deficiências do Desenvolvimento/epidemiologia , Insuficiência de Crescimento/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Otite Média/epidemiologia , Fenótipo , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
4.
JPEN J Parenter Enteral Nutr ; 40(2): 226-34, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25139979

RESUMO

BACKGROUND: This study's objective was to determine if parenteral cysteine when compared with isonitrogenous noncysteine supplementation increases erythrocyte reduced glutathione (GSH) in neonates at high risk for inflammatory injury. MATERIAL AND METHODS: Neonates with a score for neonatal acute physiology >10 requiring mechanical ventilation and parenteral nutrition (PN) were randomized in a double-blinded, placebo-controlled study to receive parenteral cysteine-HCl (CYS group) or additional PN amino acids (ISO group) at 121 mg/kg/d for ≥7 days. A 6-hour [(13)C2] glycine IV infusion was administered at study week 1 to determine the fractional synthetic rate of GSH (FSR-GSH). RESULTS: Baseline characteristics were similar between the CYS (n = 17) and ISO groups (n = 21). Erythrocyte GSH and total glutathione concentrations, GSH:oxidized GSH (GSSG), and FSR-GSH after treatment were not different between groups. However, the CYS group had a larger individual positive change in GSH and total glutathione (infusion day - baseline) compared with the ISO group (P = .02 for each). After adjusting for treatment, a lower enrollment weight and rate of red blood cell transfusion were associated with a decreased change in total glutathione and GSH (P < .05 for each). CONCLUSION: When compared with isonitrogenous noncysteine supplementation, high-dose cysteine supplementation for at least 1 week in critically ill neonates resulted in a larger and more positive individual change in GSH. Smaller infants and those who received transfused blood demonstrated less effective change in GSH with cysteine supplementation. The benefit of cysteine remains promising and deserves further investigation.


Assuntos
Estado Terminal/terapia , Cisteína/administração & dosagem , Eritrócitos/química , Glutationa/química , Aminoácidos/administração & dosagem , Doença Crônica , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eritrócitos/efeitos dos fármacos , Feminino , Glicina/administração & dosagem , Humanos , Recém-Nascido , Interleucina-6/sangue , Modelos Lineares , Pneumopatias/tratamento farmacológico , Masculino , Nutrição Parenteral , Projetos Piloto , Respiração Artificial
5.
Cell ; 156(3): 549-62, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24485460

RESUMO

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation.


Assuntos
Permeabilidade Capilar , Endotélio Vascular/metabolismo , Útero/metabolismo , Animais , Endométrio/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
6.
Blood ; 123(6): 809-21, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24227816

RESUMO

Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.


Assuntos
Fator de Transcrição GATA2/genética , Síndromes de Imunodeficiência/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Criança , Feminino , Fator de Transcrição GATA2/deficiência , Estudos de Associação Genética , Haploinsuficiência , Hematopoese , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Sistema Linfático , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
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