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BACKGROUND: Many extremely low birth weight infants develop pulmonary hypertension late in their clinical course, and over 60% go undetected by early screening echocardiography. At present, no standardised screening protocol exists for detecting late pulmonary hypertension in extremely low birth weight infants. We assessed the utility of oxygen supplementation as a predictor of late pulmonary hypertension. METHODS: A retrospective single-centre review of extremely low birth weight infants with no evidence of CHD and those surviving for >30 days was performed. The association between oxygen ⩾30% at day of life 30 and diagnosis of late pulmonary hypertension was estimated with an odds ratio and 95% confidence interval using logistic regression. Doppler echocardiography was used to diagnose pulmonary hypertension in the infants. RESULTS: A total of 230 infants met the study criteria. The incidence of late pulmonary hypertension was 8.3% (19/230). Infants with late pulmonary hypertension were more likely to have a lower mean birth weight (667.1±144 versus 799.3±140 g, p=0.001) and more likely to be small for gestational age (47.4 versus 14.2%, p=0.004). Oxygen requirement ⩾30% at day of life 30 was associated with increased risk of late pulmonary hypertension (odds ratio=3.77, 95% confidence interval=1.42-10.00, p=0.008) in univariate analysis and after adjusting for birth weight (odds ratio=2.47, 95% confidence interval=0.89-6.84, p=0.08). CONCLUSIONS: The need of oxygen supplementation ⩾30% at day of life 30 may be a good screening tool for detecting late pulmonary hypertension in extremely low birth weight infants.
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Displasia Broncopulmonar/epidemiologia , Hipertensão Pulmonar/diagnóstico , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido Prematuro , Triagem Neonatal/métodos , Oxigênio/administração & dosagem , Peso ao Nascer , Displasia Broncopulmonar/complicações , Ecocardiografia Doppler , Feminino , Florida , Idade Gestacional , Humanos , Incidência , Lactente , Mortalidade Infantil , Recém-Nascido , Modelos Logísticos , Masculino , Razão de Chances , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, causes preterm birth in animals and has been implicated as a factor triggering preterm labor and systemic complications in humans. Little is known regarding LPS in the cord blood (CB) of term and preterm infants and its association with maternal and fetal characteristics. METHODS: CB was obtained from term (n = 15) and preterm infants (n = 76) after delivery. Plasma levels of LPS, C-reactive protein (CRP), and soluble CD14 (sCD14) were measured using commercially available kits (limulus amebocyte lysate and enzyme-linked immunosorbent assay). Four linear regression models were created in order to identify independent variables that predict plasma LPS levels. RESULTS: The analyte levels were significantly higher in preterm vs. term infant CB: LPS (24.48 vs. 1 pg/ml; P = 0.0009), CRP (87.9 vs. 47 ng/ml; P = 0.01), and sCD14 (0.32 vs.0.35 µg/ml; P = 0.013). There was a (significant) positive correlation between CB LPS levels and gestational age, birth weight, CRP levels, sCD14 levels, and association with both clinical and histological chorioamnionitis. CONCLUSION: Our data suggest that LPS is associated with preterm labor and inflammation (CRP elevation and chorioamnionitis). These findings may be relevant to the understanding of the role of LPS in prematurity and its role in preterm morbidities.
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Corioamnionite/sangue , Sangue Fetal/metabolismo , Receptores de Lipopolissacarídeos/sangue , Lipopolissacarídeos/sangue , Adulto , Peso ao Nascer , Proteína C-Reativa/metabolismo , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez , Adulto JovemRESUMO
MgSO(4) exposure before preterm birth is neuroprotective, reducing the risk of cerebral palsy and major motor dysfunction. Neonatal inflammatory cytokine levels correlate with neurologic outcome, leading us to assess the effect of MgSO(4) on cytokine production in humans. We found reduced maternal TNF-α and IL-6 production following in vivo MgSO(4) treatment. Short-term exposure to a clinically effective MgSO(4) concentration in vitro substantially reduced the frequency of neonatal monocytes producing TNF-α and IL-6 under constitutive and TLR-stimulated conditions, decreasing cytokine gene and protein expression, without influencing cell viability or phagocytic function. In summary, MgSO(4) reduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. By probing the mechanism of decreased cytokine production, we found that the immunomodulatory effect was mediated by magnesium and not the sulfate moiety, and it was reversible. Cellular magnesium content increased rapidly upon MgSO(4) exposure, and reduced cytokine production occurred following stimulation with different TLR ligands as well as when magnesium was added after TLR stimulation, strongly suggesting that magnesium acts intracellularly. Magnesium increased basal IĸBα levels, and upon TLR stimulation was associated with reduced NF-κB activation and nuclear localization. These findings establish a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis.
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Fatores Imunológicos/farmacologia , Imunomodulação/imunologia , Inflamação/imunologia , Sulfato de Magnésio/farmacologia , Monócitos/efeitos dos fármacos , Western Blotting , Células Cultivadas , Citocinas/biossíntese , Feminino , Sangue Fetal/efeitos dos fármacos , Sangue Fetal/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Recém-Nascido , Recém-Nascido Prematuro/imunologia , Monócitos/imunologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV(+) patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.
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Regulação da Expressão Gênica , Infecções por HIV/sangue , Monócitos/metabolismo , Tromboplastina/biossíntese , Trombose/sangue , Adulto , Biomarcadores/sangue , Células Cultivadas , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/imunologia , Flagelina/farmacologia , HIV/imunologia , HIV/metabolismo , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Humanos , Interleucina-6/sangue , Interleucina-6/imunologia , Receptores de Lipopolissacarídeos/sangue , Receptores de Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Monócitos/imunologia , Fatores de Risco , Tromboplastina/imunologia , Trombose/etiologia , Trombose/imunologia , Trombose/mortalidade , Replicação Viral/imunologiaRESUMO
INTRODUCTION: Inflammation and infection are associated with premature birth and with activation of the fetal immune system. We hypothesized that exposure to microbial Toll-like receptor (TLR) ligands plays an important role in neonatal T-cell maturation and that early exposure to microbial products may result in early T-cell maturation and a tendency for these matured effector cells to change their homing receptor patterns. RESULTS: Expression of the CD45RO marker was induced in term neonatal T cells after in vitro exposure to TLR ligands for 7 days. Interestingly, naive T cells from adult blood were unaffected by TLR ligand exposure. In addition, neonatal T cells had more cells with decreased expression of the α4ß7 integrins and increased expression of CCR4 after in vitro exposure of TLR ligands-similar to the expression of these molecules in adult naive T cells. DISCUSSION: These findings are relevant for the understanding of neonatal T-cell maturation and may contribute to our understanding of multiorgan inflammatory complications of prematurity. METHODS: Cord blood was obtained from term and preterm infants. Using flow cytometry, we identified a mature (CD45RO(+)) phenotype in preterm infant cord blood (CB) T cells that had decreased expression of the α4ß7 integrins and increased expression of the C-C chemokine receptor 4 (CCR4) as compared with term infant CB.
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Envelhecimento/imunologia , Recém-Nascido Prematuro/imunologia , Nascimento Prematuro/imunologia , Receptores de Retorno de Linfócitos/metabolismo , Linfócitos T/imunologia , Receptores Toll-Like/metabolismo , Adulto , Fatores Etários , Estudos de Casos e Controles , Células Cultivadas , Corioamnionite/imunologia , Corioamnionite/microbiologia , Feminino , Sangue Fetal/imunologia , Citometria de Fluxo , Idade Gestacional , Humanos , Fatores Imunológicos/farmacologia , Memória Imunológica , Imunofenotipagem , Recém-Nascido , Recém-Nascido Prematuro/sangue , Integrinas/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Ligantes , Ativação Linfocitária , Fenótipo , Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/microbiologia , Receptores CCR4/metabolismo , Receptores de Retorno de Linfócitos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Receptores Toll-Like/agonistas , Estados UnidosRESUMO
The very low birth weight (VLBW) infant is at great risk for marked dysbiosis of the gut microbiome due to multiple factors, including physiological immaturity and prenatal/postnatal influences that disrupt the development of a normal gut flora. However, little is known about the developmental succession of the microbiota in preterm infants as they grow and mature. This review provides a synthesis of our understanding of the normal development of the infant gut microbiome and contrasts this with dysbiotic development in the VLBW infant. The role of human milk in normal gut microbial development is emphasized, along with the role of the gut microbiome in immune development and gastroenteric health. Current research provides evidence that the gut microbiome interacts extensively with many physiological systems and metabolic processes in the developing infant. However, to the best of our knowledge, there are currently no studies prospectively mapping the gut microbiome of VLBW infants through early childhood. This knowledge gap must be filled to inform a healthcare system that can provide for the growth, health, and development of VLBW infants. The paper concludes with speculation about how the VLBW infants' gut microbiome might function through host-microbe interactions to contribute to the sequelae of preterm birth, including its influence on growth, development, and general health of the infant host.
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Regulatory T cells are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens. The purpose of this study was to measure the percentages of two different regulatory T cells subpopulations, identified by the presence or absence of CD31 (Recent thymic emigrants and peripherally induced naïve regulatory T cells), in term and preterm infant cord blood. We report the association of prenatal factors, intrauterine exposure to lipopolysaccharide and inflammation and the percentages of these regulatory T cell subpopulations in term and preterm infants. Cord blood samples were collected from both term and preterm infants and mononuclear cells isolated over a Ficoll-Hypaque cushion. Cells were then stained with fluorochrome-labeled antibodies to characterize regulatory T cell populations and analyzed with multi-color flow cytometry. Cord blood plasma C-reactive protein, and lipopolysaccharide were also measured. Placental pathology was also examined. We report a gestational age-dependent difference in the percentage of total regulatory T cells, in which preterm infants of lower gestational ages have an increased percentage of regulatory T cells. We report the presence of two populations of regulatory T cells (CD31+ and CD31-) in cord blood of term and preterm infants and their association with different maternal and fetal characteristics. Factors associated with differences in the percentage of CD31- Tregs included the use of prenatal antibiotics, steroids and magnesium sulfate. In addition, the percentage of CD31- Tregs was significantly higher in cord blood of preterm pregnancies associated with inflammation and prenatal lipopolysaccharide exposure. The peripheral Treg pool of preterm infants could be altered by prenatal exposure to inflammation and chorioamnionitis; however, the clinical implications of this finding are not yet understood.
Assuntos
Recém-Nascido Prematuro , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Nascimento Prematuro/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Feminino , Sangue Fetal/imunologia , Citometria de Fluxo , Humanos , Recém-Nascido , Recém-Nascido Prematuro/sangue , Recém-Nascido Prematuro/imunologia , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/efeitos adversos , Masculino , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Nascimento Prematuro/sangue , Nascimento Prematuro/induzido quimicamente , Esteroides/administração & dosagem , Esteroides/efeitos adversos , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND: Preterm parturition is characterized by innate immune activation and increased proinflammatory cytokine levels. This well established association leads us to hypothesize that preterm delivery is also associated with neonatal T lymphocyte activation and maturation. METHODOLOGY/PRINCIPAL FINDINGS: Cord blood samples were obtained following term, preterm, and deliveries complicated by clinical chorioamnionitis. Activation marker expression was quantitated by flow cytometric analysis. Infants born following preterm delivery demonstrated enhanced CD4(+) T lymphocyte activation, as determined by CD25 (Term 9.72% vs. Preterm 17.67%, pâ=â0.0001), HLA-DR (Term 0.91% vs. Preterm 1.92%, pâ=â0.0012), and CD69 expression (Term 0.38% vs. Preterm 1.20%, pâ=â0.0003). Neonates delivered following clinical chorioamnionitis also demonstrated increased T cell activation. Preterm neonates had an increased frequency of CD45RO(+) T cells. CONCLUSION/SIGNIFICANCE: Preterm parturition is associated with neonatal CD4(+) T cell activation, and an increased frequency of CD45RO(+) T cells. These findings support the concept that activation of the fetal adaptive immune system in utero is closely associated with preterm labor.
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Corioamnionite/imunologia , Trabalho de Parto Prematuro/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Adulto , Corioamnionite/metabolismo , Feminino , Feto/imunologia , Humanos , Recém-Nascido , Antígenos Comuns de Leucócito/metabolismo , Trabalho de Parto Prematuro/metabolismo , Gravidez , Linfócitos T/metabolismoRESUMO
HIV infection results in depletion and dysfunction of naïve CD4(+) T cells. The mechanisms underlying these deficiencies are not understood. We investigated the frequencies of CD4(+) naïve subsets in HIV disease as defined by expression of CD25 and/or FoxP3 and the relationship of these frequencies to naïve T cell proliferation function. We observed increased proportions of CD25(+)FoxP3(+) and CD25(+)FoxP3(-) cells and decreased proportions of CD25(-)FoxP3(-) cells within the naïve CD4(+) cell compartment from HIV-infected persons compared with findings in healthy donors. These perturbations were related to higher plasma HIV RNA levels but not with higher immune activation, as measured by the proportions of CD38(+) memory CD4(+) T cells. Naïve T cell proliferation responses to mitogen stimulation were inversely related to the frequencies and absolute numbers of FoxP3(+) naïve T cells. MDA, a marker of oxidative stress, and sCD14, a marker of monocyte activation and a surrogate for microbial translocation, were increased in serum samples from HIV(+) donors; however, neither marker was related to naïve T cell function in HIV(+) donors. These observations suggest that alterations in naïve T cell subset frequencies could contribute to naïve T cell dysfunction in HIV disease, but these alterations are not necessarily the result of chronic immune activation.
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Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/metabolismo , Linfócitos T Reguladores/imunologia , Carga Viral , Adulto , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Citocinas/metabolismo , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/metabolismo , Humanos , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/virologiaRESUMO
BACKGROUND: Recently, heightened systemic translocation of microbial products was found in persons with chronic HIV infection and this was linked to immune activation and CD4(+) T cell homeostasis. METHODOLOGY: We examined here the effects of microbial Toll-like receptor (TLR) ligands on T cell activation in vitro. CONCLUSIONS/FINDINGS: We show that exposure to TLR ligands results in activation of memory and effector CD4(+) and CD8(+) T cells. After exposure to each of 8 different ligands that activate TLRs 2, 3, 4, 5, 7, 8, and 9, CD8(+) T cells are activated and gain expression of the C type lectin CD69 that may promote their retention in lymphoid tissues. In contrast, CD4(+) T cells rarely increase CD69 expression but instead enter cell cycle. Despite activation and cell cycle entry, CD4(+) T cells divide poorly and instead, disproportionately undergo activation-induced cell death. Systemic exposure to TLR agonists may therefore increase immune activation, effector cell sequestration in lymphoid tissues and T cell turnover. These events may contribute to the pathogenesis of immune dysfunction and CD4+ T cell losses in chronic infection with the human immunodeficiency virus.
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Infecções por HIV/metabolismo , HIV/metabolismo , Linfócitos T/metabolismo , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos T/biossíntese , Apoptose , Linfócitos T CD4-Positivos/metabolismo , Ciclo Celular , Morte Celular , Proliferação de Células , Flagelina/metabolismo , Homeostase , Humanos , Lectinas Tipo C , Leucócitos Mononucleares/metabolismo , Ligantes , Lipopolissacarídeos/metabolismoRESUMO
Many immunological defects have been described in HIV disease, including a diminished capacity of naive CD4+ T cells to expand after TCR stimulation. The mechanisms underlying impaired naive CD4+ T cell expansion in HIV disease are not well described. Using a rigorous phenotypic definition of naive T cells, we found that cell cycle entry after TCR engagement was restricted to cells that increased surface expression of costimulatory molecules CD27 and CD28. Induction of these receptors, however, was not sufficient to result in cell cycle entry among the CD4+CD31- naive T cell subset. Analyses of cells from HIV-infected persons indicated that naive CD4+CD31+ T cells from these subjects were impaired in their ability to enter the cell cycle after stimulation and this impairment was predicted by the relatively poor induction of costimulatory molecules on these cells. Thus, failure to increase surface expression of costimulatory molecules may contribute to the naive T cell expansion failure that characterizes HIV infection.