Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
Mais filtros

Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 184(3): 628-642.e10, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33476549

RESUMO

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Complicações Infecciosas na Gravidez/imunologia , SARS-CoV-2/imunologia , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Terceiro Trimestre da Gravidez/imunologia , Receptores de IgG/imunologia , Células THP-1
2.
Cell ; 182(3): 542-544, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32763186

RESUMO

Serotonin production by enterochromaffin cells (ECs) is microbiota-dependent, but the mechanism of this is unknown. In this issue of Cell, Sugisawa et al. demonstrate that Piezo1 in ECs senses single-strand RNA (ssRNA) from intestinal microbiota to promote serotonin production. Deletion of Piezo1 in intestinal epithelium promotes bone formation, decreases peristalsis, and protects from colitis because of decreased serotonin.


Assuntos
Microbioma Gastrointestinal , Serotonina , Células Enterocromafins , Canais Iônicos/genética , RNA
3.
Immunity ; 56(5): 1115-1131.e9, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-36917985

RESUMO

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.


Assuntos
Estresse do Retículo Endoplasmático , Mucosa Intestinal , Células Th17 , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Diferenciação Celular , Humanos , Animais , Camundongos , Camundongos Transgênicos , Antibacterianos/farmacologia
4.
Pediatr Res ; 91(5): 1090-1098, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34750520

RESUMO

BACKGROUND: During the COVID-19 pandemic, thousands of pregnant women have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The implications of maternal SARS-CoV-2 infection on fetal and childhood well-being need to be characterized. We aimed to characterize the fetal immune response to maternal SARS-CoV-2 infection. METHODS: We performed single-cell RNA-sequencing and T cell receptor sequencing on cord blood mononuclear cells (CBMCs) from newborns of mothers infected with SARS-CoV-2 in the third trimester (cases) or without SARS-CoV-2 infection (controls). RESULTS: We identified widespread gene expression changes in CBMCs from cases, including upregulation of interferon-stimulated genes and major histocompatibility complex genes in CD14+ monocytes, transcriptional changes suggestive of activation of plasmacytoid dendritic cells, and activation and exhaustion of natural killer cells. Lastly, we observed fetal T cell clonal expansion in cases compared to controls. CONCLUSIONS: As none of the infants were infected with SARS-CoV-2, our results suggest that maternal SARS-CoV-2 infection might modulate the fetal immune system in the absence of vertical transmission. IMPACT: The implications of maternal SARS-CoV-2 infection in the absence of vertical transmission on fetal and childhood well-being are poorly understood. Maternal SARS-CoV-2 infection might modulate the fetal immune system in the absence of vertical transmission. This study raises important questions about the untoward effects of maternal SARS-CoV-2 on the fetus, even in the absence of vertical transmission.


Assuntos
COVID-19 , Complicações Infecciosas na Gravidez , Criança , Feminino , Feto , Humanos , Imunidade , Imunofenotipagem , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Pandemias , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , SARS-CoV-2
5.
Proc Natl Acad Sci U S A ; 116(47): 23671-23681, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690657

RESUMO

Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/imunologia , Estresse do Retículo Endoplasmático/imunologia , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1d/biossíntese , Antígenos CD1d/imunologia , Autoantígenos/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Citoesqueleto/ultraestrutura , Endossomos/imunologia , Glicoesfingolipídeos/imunologia , Glicoesfingolipídeos/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Lipídeos/imunologia , Lisossomos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células THP-1 , Tapsigargina/farmacologia , Resposta a Proteínas não Dobradas/imunologia , eIF-2 Quinase/deficiência , eIF-2 Quinase/fisiologia
7.
BMC Med Res Methodol ; 20(1): 228, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917141

RESUMO

BACKGROUND: COVID-19, the disease caused by the highly infectious and transmissible coronavirus SARS-CoV-2, has quickly become a morbid global pandemic. Although the impact of SARS-CoV-2 infection in children is less clinically apparent, collecting high-quality biospecimens from infants, children, and adolescents in a standardized manner during the COVID-19 pandemic is essential to establish a biologic understanding of the disease in the pediatric population. This biorepository enables pediatric centers world-wide to collect samples uniformly to drive forward our understanding of COVID-19 by addressing specific pediatric and neonatal COVID-19-related questions. METHODS: A COVID-19 biospecimen collection study was implemented with strategic enrollment guidelines to include patients seen in urgent care clinics and hospital settings, neonates born to SARS-CoV-2 infected mothers, and asymptomatic children. The methodology described here, details the importance of establishing collaborations between the clinical and research teams to harmonize protocols for patient recruitment and sample collection, processing and storage. It also details modifications required for biobanking during a surge of the COVID-19 pandemic. RESULTS: Considerations and challenges facing enrollment of neonatal and pediatric cohorts are described. A roadmap is laid out for successful collection, processing, storage and database management of multiple pediatric samples such as blood, nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine. Using this methodology, we enrolled 327 participants, who provided a total of 972 biospecimens. CONCLUSIONS: Pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal SARS-CoV-2 infection on fetal development, and factors driving the Multisystem Inflammatory Syndrome in Children. The specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to SARS-CoV-2 infection and disease abnormalities. The successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies.


Assuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Manejo de Espécimes/métodos , Adolescente , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Feminino , Desenvolvimento Fetal , Hospitalização , Humanos , Lactente , Recém-Nascido , Masculino , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , SARS-CoV-2
8.
BMC Med Res Methodol ; 20(1): 215, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842979

RESUMO

BACKGROUND: Collection of biospecimens is a critical first step to understanding the impact of COVID-19 on pregnant women and newborns - vulnerable populations that are challenging to enroll and at risk of exclusion from research. We describe the establishment of a COVID-19 perinatal biorepository, the unique challenges imposed by the COVID-19 pandemic, and strategies used to overcome them. METHODS: A transdisciplinary approach was developed to maximize the enrollment of pregnant women and their newborns into a COVID-19 prospective cohort and tissue biorepository, established on March 19, 2020 at Massachusetts General Hospital (MGH). The first SARS-CoV-2 positive pregnant woman was enrolled on April 2, and enrollment was expanded to SARS-CoV-2 negative controls on April 20. A unified enrollment strategy with a single consent process for pregnant women and newborns was implemented on May 4. SARS-CoV-2 status was determined by viral detection on RT-PCR of a nasopharyngeal swab. Wide-ranging and pregnancy-specific samples were collected from maternal participants during pregnancy and postpartum. Newborn samples were collected during the initial hospitalization. RESULTS: Between April 2 and June 9, 100 women and 78 newborns were enrolled in the MGH COVID-19 biorepository. The rate of dyad enrollment and number of samples collected per woman significantly increased after changes to enrollment strategy (from 5 to over 8 dyads/week, P < 0.0001, and from 7 to 9 samples, P < 0.01). The number of samples collected per woman was higher in SARS-CoV-2 negative than positive women (9 vs 7 samples, P = 0.0007). The highest sample yield was for placenta (96%), umbilical cord blood (93%), urine (99%), and maternal blood (91%). The lowest-yield sample types were maternal stool (30%) and breastmilk (22%). Of the 61 delivered women who also enrolled their newborns, fewer women agreed to neonatal blood compared to cord blood (39 vs 58, P < 0.0001). CONCLUSIONS: Establishing a COVID-19 perinatal biorepository required patient advocacy, transdisciplinary collaboration and creative solutions to unique challenges. This biorepository is unique in its comprehensive sample collection and the inclusion of a control population. It serves as an important resource for research into the impact of COVID-19 on pregnant women and newborns and provides lessons for future biorepository efforts.


Assuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/psicologia , Participação do Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/psicologia , Complicações Infecciosas na Gravidez/diagnóstico , Manejo de Espécimes , Adulto , COVID-19 , Feminino , Humanos , Recém-Nascido , Pandemias , Seleção de Pacientes , Assistência Perinatal , Gravidez , Complicações Infecciosas na Gravidez/psicologia , SARS-CoV-2
10.
J Immunol ; 189(8): 3800-4, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22984083

RESUMO

Phagocyte NADPH oxidase plays a key role in pathogen clearance via reactive oxygen species (ROS) production. Defects in oxidase function result in chronic granulomatous disease with hallmark recurrent microbial infections and inflammation. The oxidase's role in the adaptive immune response is not well understood. Class II presentation of cytoplasmic and exogenous Ag to CD4(+) T cells was impaired in human B cells with reduced oxidase p40(phox) subunit expression. Naturally arising mutations, which compromise p40(phox) function in a chronic granulomatous disease patient, also perturbed class II Ag presentation and intracellular ROS production. Reconstitution of patient B cells with a wild-type, but not a mutant, p40(phox) allele restored exogenous Ag presentation and intracellular ROS generation. Remarkably, class II presentation of epitopes from membrane Ag was robust in p40(phox)-deficient B cells. These studies reveal a role for NADPH oxidase and p40(phox) in skewing epitope selection and T cell recognition of self Ag.


Assuntos
Apresentação de Antígeno/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Antígenos HLA-DR/metabolismo , NADPH Oxidases/fisiologia , Apresentação de Antígeno/genética , Subpopulações de Linfócitos B/enzimologia , Linhagem Celular Transformada , Humanos , Líquido Intracelular/enzimologia , Líquido Intracelular/imunologia , Líquido Intracelular/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Fosfoproteínas/biossíntese , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/genética , Regulação para Cima/imunologia
11.
J Exp Med ; 220(11)2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37695524

RESUMO

Epithelial cells play a crucial role in barrier defense. Here, Moniruzzaman et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230106) discovered that interleukin-22 (IL-22) represses MHC class II expression by epithelial cells with an opposite impact on chronic inflammatory disease and viral infection.


Assuntos
Células Epiteliais , Interleucinas , Genes MHC da Classe II , Interleucina 22
12.
STAR Protoc ; 4(3): 102485, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37566548

RESUMO

Studying gene function in T cells is crucial for understanding physiology and disease pathogenesis. Here, we provide a protocol to examine the role of specific genes in CD4+ T cell differentiation in the intestine. We describe steps for isolating naïve CD4+ T cells from mouse spleens and transferring them to recipient mice. We detail procedures to isolate lamina propria cells and analyze CD4+ T subsets using flow cytometry. This protocol is useful in the study of mucosal immune functions. For complete details on the use and execution of this protocol, please refer to Duan et al.1.


Assuntos
Linfócitos T CD4-Positivos , Mucosa , Animais , Camundongos , Citometria de Fluxo , Diferenciação Celular , Intestino Delgado
13.
J Exp Med ; 220(1)2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36413219

RESUMO

Intelectin-1 (ITLN1) is a lectin secreted by intestinal epithelial cells (IECs) and upregulated in human ulcerative colitis (UC). We investigated how ITLN1 production is regulated in IECs and the biological effects of ITLN1 at the host-microbiota interface using mouse models. Our data show that ITLN1 upregulation in IECs from UC patients is a consequence of activating the unfolded protein response. Analysis of microbes coated by ITLN1 in vivo revealed a restricted subset of microorganisms, including the mucolytic bacterium Akkermansia muciniphila. Mice overexpressing intestinal ITLN1 exhibited decreased inner colonic mucus layer thickness and closer apposition of A. muciniphila to the epithelial cell surface, similar to alterations reported in UC. The changes in the inner mucus layer were microbiota and A. muciniphila dependent and associated with enhanced sensitivity to chemically induced and T cell-mediated colitis. We conclude that by determining the localization of a select group of bacteria to the mucus layer, ITLN1 modifies this critical barrier. Together, these findings may explain the impact of ITLN1 dysregulation on UC pathogenesis.


Assuntos
Colite Ulcerativa , Verrucomicrobia , Humanos , Camundongos , Animais , Verrucomicrobia/metabolismo , Muco/metabolismo , Lectinas , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia
14.
Nat Biomed Eng ; 6(4): 476-494, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35314801

RESUMO

The cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia.


Assuntos
Organoides , Celulas de Paneth , Animais , Diferenciação Celular , Intestinos , Camundongos , Celulas de Paneth/fisiologia , Células-Tronco
15.
Pediatrics ; 150(4)2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36164852

RESUMO

OBJECTIVES: Necrotizing enterocolitis (NEC) is a severe intestinal inflammatory disease and a leading cause of morbidity and mortality in NICUs. Management of NEC is variable because of the lack of evidence-based recommendations. It is widely accepted that standardization of patient care leads to improved outcomes. This quality improvement project aimed to decrease variation in the evaluation and management of NEC in a Level IV NICU. METHODS: A multidisciplinary team investigated institutional variation in NEC management and developed a standardized guideline and electronic medical record tools to assist in evaluation and management. Retrospective baseline data were collected for 2 years previously and prospectively for 3.5 years after interventions. Outcomes included the ratio of observed-to-expected days of antibiotics and nil per os (NPO) on the basis of the novel guidelines and the percentage of cases treated with piperacillin/tazobactam. Balancing measures were death, surgery, and antifungal use. RESULTS: Over 5.5 years, there were 124 evaluations for NEC. Special cause variation was noted in the observed-to-expected antibiotic and NPO days ratios, decreasing from 1.94 to 1.18 and 1.69 to 1.14, respectively. Piperacillin/tazobactam utilization increased from 30% to 91%. There were no increases in antifungal use, surgery, or death. CONCLUSIONS: Variation in evaluation and management of NEC decreased after initiation of a guideline and supporting electronic medical record tools, with fewer antibiotic and NPO days without an increase in morbidity or mortality. A quality improvement approach can benefit patients and decrease variability, even in diseases with limited evidence-based standards.


Assuntos
Enterocolite Necrosante , Doenças Fetais , Doenças do Recém-Nascido , Antibacterianos/uso terapêutico , Antifúngicos , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/terapia , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Piperacilina , Estudos Retrospectivos , Tazobactam
16.
Blood ; 114(15): 3309-15, 2009 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-19692703

RESUMO

Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91(phox) and p22(phox), which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47(phox) and p67(phox). A fifth subunit, p40(phox), plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40(phox), in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40(phox)R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40(phox)-deficient granulocytes, with premature loss of p40(phox)R105Q from phagosomes. Thus, p40(phox) binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.


Assuntos
Códon de Terminação , Genes Recessivos , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Doença Granulomatosa Crônica/enzimologia , Doença Granulomatosa Crônica/genética , Mutação de Sentido Incorreto , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/enzimologia , Adulto , Substituição de Aminoácidos , Carcinógenos , Linhagem Celular Tumoral , Criança , Análise Mutacional de DNA , Feminino , Doença Granulomatosa Crônica/patologia , Heterozigoto , Humanos , Masculino , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/patologia , Fagocitose/genética , Ésteres de Forbol , Fosfatos de Fosfatidilinositol , Superóxidos/metabolismo
17.
Pediatrics ; 147(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33483452

RESUMO

The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration-approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006-April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.


Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Enterocolite Necrosante/induzido quimicamente , Diazóxido/uso terapêutico , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/epidemiologia , Evolução Fatal , Feminino , Humanos , Incidência , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/induzido quimicamente , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/tratamento farmacológico , Doenças do Prematuro/epidemiologia , Masculino , Estudos Retrospectivos , Fatores de Risco
18.
Res Sq ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32818214

RESUMO

Background: COVID-19, the disease caused by the highly infectious and transmissible coronavirus SARS-CoV-2, has quickly become a morbid global pandemic. Although the impact of SARS-CoV-2 infection in children is less clinically apparent, collecting high-quality biospecimens from infants, children, and adolescents in a standardized manner during the COVID-19 pandemic is essential to establish a biologic understanding of the disease in the pediatric population. This biorepository enables pediatric centers world-wide to collect samples uniformly to drive forward our understanding of COVID-19 by addressing specific pediatric and neonatal COVID-19-related questions. Methods: A COVID-19 biospecimen collection study was implemented with strategic enrollment guidelines to include patients seen in urgent care clinics and hospital settings, neonates born to SARS-CoV-2 infected mothers, and asymptomatic children. The methodology described here, details the importance of establishing collaborations between the clinical and research teams to harmonize protocols for patient recruitment and sample collection, processing and storage. It also details modifications required for biobanking during a surge of the COVID-19 pandemic. Results: Considerations and challenges facing enrollment of neonatal and pediatric cohorts are described. A roadmap is laid out for successful collection, processing, storage and database management of multiple pediatric samples such as blood, nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine. Using this methodology, we enrolled 327 participants, who provided a total of 972 biospecimens. Conclusions: Pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal SARS-CoV-2 infection on fetal development, and factors driving the Multisystem Inflammatory Syndrome in Children. The specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to SARS-CoV-2 infection and disease abnormalities. The successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies.

19.
JAMA Netw Open ; 3(12): e2030455, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351086

RESUMO

Importance: Biological data are lacking with respect to risk of vertical transmission and mechanisms of fetoplacental protection in maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objective: To quantify SARS-CoV-2 viral load in maternal and neonatal biofluids, transplacental passage of anti-SARS-CoV-2 antibody, and incidence of fetoplacental infection. Design, Setting, and Participants: This cohort study was conducted among pregnant women presenting for care at 3 tertiary care centers in Boston, Massachusetts. Women with reverse transcription-polymerase chain reaction (RT-PCR) results positive for SARS-CoV-2 were recruited from April 2 to June 13, 2020, and follow-up occurred through July 10, 2020. Contemporaneous participants without SARS-CoV-2 infection were enrolled as a convenience sample from pregnant women with RT-PCR results negative for SARS-CoV-2. Exposures: SARS-CoV-2 infection in pregnancy, defined by nasopharyngeal swab RT-PCR. Main Outcomes and Measures: The main outcomes were SARS-CoV-2 viral load in maternal plasma or respiratory fluids and umbilical cord plasma, quantification of anti-SARS-CoV-2 antibodies in maternal and cord plasma, and presence of SARS-CoV-2 RNA in the placenta. Results: Among 127 pregnant women enrolled, 64 with RT-PCR results positive for SARS-CoV-2 (mean [SD] age, 31.6 [5.6] years) and 63 with RT-PCR results negative for SARS-CoV-2 (mean [SD] age, 33.9 [5.4] years) provided samples for analysis. Of women with SARS-CoV-2 infection, 23 (36%) were asymptomatic, 22 (34%) had mild disease, 7 (11%) had moderate disease, 10 (16%) had severe disease, and 2 (3%) had critical disease. In viral load analyses among 107 women, there was no detectable viremia in maternal or cord blood and no evidence of vertical transmission. Among 77 neonates tested in whom SARS-CoV-2 antibodies were quantified in cord blood, 1 had detectable immunoglobuilin M to nucleocapsid. Among 88 placentas tested, SARS-CoV-2 RNA was not detected in any. In antibody analyses among 37 women with SARS-CoV-2 infection, anti-receptor binding domain immunoglobin G was detected in 24 women (65%) and anti-nucleocapsid was detected in 26 women (70%). Mother-to-neonate transfer of anti-SARS-CoV-2 antibodies was significantly lower than transfer of anti-influenza hemagglutinin A antibodies (mean [SD] cord-to-maternal ratio: anti-receptor binding domain immunoglobin G, 0.72 [0.57]; anti-nucleocapsid, 0.74 [0.44]; anti-influenza, 1.44 [0.80]; P < .001). Nonoverlapping placental expression of SARS-CoV-2 receptors angiotensin-converting enzyme 2 and transmembrane serine protease 2 was noted. Conclusions and Relevance: In this cohort study, there was no evidence of placental infection or definitive vertical transmission of SARS-CoV-2. Transplacental transfer of anti-SARS-CoV-2 antibodies was inefficient. Lack of viremia and reduced coexpression and colocalization of placental angiotensin-converting enzyme 2 and transmembrane serine protease 2 may serve as protective mechanisms against vertical transmission.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Sangue Fetal/imunologia , Imunidade Materno-Adquirida/imunologia , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Placenta/metabolismo , Complicações Infecciosas na Gravidez/imunologia , SARS-CoV-2/imunologia , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/sangue , COVID-19/transmissão , Teste Sorológico para COVID-19 , Estudos de Casos e Controles , Estudos de Coortes , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Feminino , Sangue Fetal/virologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Recém-Nascido , Vírus da Influenza A/imunologia , Masculino , Fosfoproteínas/imunologia , Placenta/patologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Estudos Prospectivos , RNA Viral/metabolismo , Receptores de Coronavírus/metabolismo , Serina Endopeptidases/metabolismo , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA