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1.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(9): 1071-1076, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31594148

RESUMO

Objective: To investigate the expression of IL-18 in peripheral blood of HBsAg positive parturients in intrauterine transmission of HBV. Methods: A case-control study was conducted in 282 HBsAg positive parturients and 43 health parturients (control group) in Northwest Women and Children Hospital of Shaanxi Province. Enzyme-linked immunosorbent assay (ELISA) was used to detect five serological makers of hepatitis B, real time PCR was used to detect HBV DNA, and flow liquid chip method was used to detect IL-18 levels in peripheral blood of parturients and newborns. Results: The incidence of dominant HBV infection (DBI), occult HBV infection (OBI) and intrauterine transmission of HBV were 8.42% (24/285), 40.00% (114/285) and 48.42% (138/285), respectively. The level of IL-18 in peripheral blood of HBsAg-negative parturients were significantly lower than those of HBsAg-positive parturients (P=0.001), non-HBV intrauterine transmission (NBIT) group (P=0.001) and OBI group (P<0.001). The level of IL-18 in HBeAg negative group was significantly lower than that in HBeAg positive group (P=0.023). When HBV DNA load was ≥10(3) copies/ml, the level of IL-18 was significantly higher than that in HBsAg-negative group (P<0.01). With the increase of HBV DNA load in maternal blood, the level of IL-18 increased (P=0.024). When HBV DNA load was 10(3)-10(6) copies/ml, the level of IL-18 in DBI group was significantly lower than that in NBIT group (P=0.022), and increased with the increase of HBV DNA load in maternal blood (P=0.016). With the increased severity of intrauterine transmission of HBV, the level of IL-18 in non-hepatitis B vaccine group decreased significantly (P=0.044). The level of IL-18 in non-hepatitis B vaccine group and immunoglobulin injection group was significantly higher than that in NBIT group (P<0.05). Multivariate analysis showed that the linear relationship between maternal HBeAg status and maternal IL-18 levels had statistical significance (P=0.01). Conclusions: IL-18 is a higher level balance regulator of Th1/Th2 immune network. Monitoring the level of IL-18 in HBsAg-positive parturients can be used not only for predicting the probability of DBI and OBI, but also as an intervention mean, especially for those who are HBeAg-positive and had HBV DNA load ≥10(3) copies/ml, to improve maternal cellular immune function, which is conducive to interrupting intrauterine transmission and providing a theoretical basis for the prevention and control of HBV intrauterine transmission.


Assuntos
Hepatite B/metabolismo , Interleucina-18/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Estudos de Casos e Controles , Criança , Correlação de Dados , DNA Viral , Feminino , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Gravidez , Complicações Infecciosas na Gravidez/virologia
2.
Nat Commun ; 10(1): 4155, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519912

RESUMO

Zika virus (ZIKV) infection results in an increased risk of spontaneous abortion and poor intrauterine growth although the underlying mechanisms remain undetermined. Little is known about the impact of ZIKV infection during the earliest stages of pregnancy, at pre- and peri-implantation, because most current ZIKV pregnancy studies have focused on post-implantation stages. Here, we demonstrate that trophectoderm cells of pre-implantation human and mouse embryos can be infected with ZIKV, and propagate virus causing neural progenitor cell death. These findings are corroborated by the dose-dependent nature of ZIKV susceptibility of hESC-derived trophectoderm cells. Single blastocyst RNA-seq reveals key transcriptional changes upon ZIKV infection, including nervous system development, prior to commitment to the neural lineage. The pregnancy rate of mice is >50% lower in pre-implantation infection than infection at E4.5, demonstrating that pre-implantation ZIKV infection leads to miscarriage. Cumulatively, these data elucidate a previously unappreciated association of pre- and peri-implantation ZIKV infection and microcephaly.


Assuntos
Complicações Infecciosas na Gravidez/metabolismo , Infecção por Zika virus/complicações , Infecção por Zika virus/metabolismo , Zika virus/patogenicidade , Aborto Espontâneo/metabolismo , Aborto Espontâneo/fisiopatologia , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Implantação do Embrião/fisiologia , Feminino , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , RNA Viral/genética , Pesquisa Médica Translacional/métodos , Trofoblastos/citologia , Trofoblastos/metabolismo
3.
Infect Dis Obstet Gynecol ; 2019: 9426795, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30692844

RESUMO

Objective: This study sought to investigate associations between serum total and free 25(OH)D and bacterial vaginosis (BV) in early and later pregnancy among US black women to provide insight into the most clinically relevant measure of vitamin D status among pregnant black women with respect to risk for BV as well as insights into critical time points for measuring and/or addressing vitamin D status in pregnancy. Methods: Data and biospecimens were derived from a subsample (N = 137) of women from the Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Cohort, for whom data related to vitamin D status (serum assays for total and free 25(OH)D) and Nugent score of Gram stained vaginal specimens in early (8-14 weeks) and later (24-30 weeks) were available. We compared total and free 25(OH)D concentrations for women according to Nugent score category (normal flora, intermediate flora, and BV) and assessed the odds of BV according to measures of vitamin D status. Results: Thirty-seven (27%) women had adequate vitamin D status at baseline, whereas 70 (51%) had insufficient vitamin D and 30 (22%) were vitamin D deficient; there were not significant differences in the proportion of women with adequate, insufficient, or deficient vitamin D according to Nugent score category. However, the odds of BV later in pregnancy were significantly higher for women who experienced a smaller rise in total 25(OH)D and free 25(OH)D from 8-14 through 24-30 weeks gestation. Conclusion: The change in measures of vitamin D status from early to later pregnancy is associated with the occurrence of BV in pregnancy. Further research is needed to examine the association between the change in vitamin D status over pregnancy and the occurrence of BV and other measures of vaginal microbial composition as well as to identify factors that influence change in vitamin D status over pregnancy.


Assuntos
Afro-Americanos , Complicações Infecciosas na Gravidez/metabolismo , Vaginose Bacteriana/metabolismo , Vitamina D/análogos & derivados , Vitaminas/metabolismo , Adolescente , Adulto , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez/sangue , Fatores de Risco , Esfregaço Vaginal , Vaginose Bacteriana/sangue , Vaginose Bacteriana/complicações , Vitamina D/sangue , Vitamina D/metabolismo , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Vitaminas/sangue , Adulto Jovem
4.
J Matern Fetal Neonatal Med ; 32(21): 3511-3519, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29720007

RESUMO

Purpose: The aim of study was to evaluate expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) in Chlamydia trachomatis (CT)-infected spontaneous aborters (SA). Materials and methods: Endometrial curettage tissue was collected from 140 SA (sporadic SA- 70; recurrent SA- 70) (Group I) and 140 age-matched controls (Group II) from Department of Obstetrics and Gynecology, Safdarjung Hospital, New Delhi, India. Polymerase chain reaction was performed for diagnosis of CT. The expression of iNOS/ eNOS/ IFN-γ/ TNF-α was assessed by real-time polymerase chain reaction (PCR). Results: 15.7% SA were CT-positive (Group I); none in controls. Sporadic spontaneous aborters (SSA) (n = 8/70), recurrent spontaneous aborters (RSA) (n = 14/70) diagnosed as CT-positive (Group-I). Significant upregulation of iNOS/ eNOS was found in CT-positive SSA/RSA compared with CT-negative SSA/RSA and healthy controls. TNF-α and IFN-γ were expressed in CT-positive SSA/RSA compared with negative SSA/controls. iNOS showed a significant strong positive correlation with TNF-α and IFN-γ in CT-infected SA. eNOS showed a significant positive correlation with TNF-α and no correlation with IFN-γ in CT-infected SA. TNF-α was positively correlated with IFN-γ. Conclusions: Significantly high expression of iNOS/ eNOS and proinflammatory cytokines affected pregnancy in CT-infected RSA, thereby implying that there occurs cytokine-induced expression of nitric oxide synthase (NOS).


Assuntos
Aborto Habitual/genética , Aborto Habitual/microbiologia , Infecções por Chlamydia/genética , Chlamydia trachomatis , Citocinas/farmacologia , Óxido Nítrico Sintase/genética , Aborto Habitual/metabolismo , Aborto Habitual/patologia , Adulto , Estudos de Casos e Controles , Infecções por Chlamydia/complicações , Infecções por Chlamydia/metabolismo , Chlamydia trachomatis/fisiologia , Endométrio/metabolismo , Endométrio/microbiologia , Endométrio/patologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/farmacologia , Interferon gama/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/genética , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Adulto Jovem
5.
Turk J Med Sci ; 48(5): 916-924, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30384554

RESUMO

Background/aim: Impaired lymphatic function is associated with pathological conditions. The presence of placental lymphatics is still under debate. This study evaluates the placental podoplanin expression in normotensive and preeclamptic women with and without HIV. Materials and methods: Normotensive (n = 60) and preeclamptic (n = 120) pregnant women were stratified into early and late onset preeclampsia and further divided by HIV status. Immunostaining was performed using the podoplanin antibody prior to the morphometric image analysis. Results: Podoplanin was immunolocalized in a reticular-like stroma complex within the exchange and conducting villi. The immunoexpression of podoplanin was significantly upregulated in the exchange villi (P = 0.001) irrespective of the pregnancy type and HIV status. Based on pregnancy type, podoplanin was downregulated in early onset preeclampsia (15.33 ± 4.27%) compared to late onset preeclampsia in the exchange villi (17.85 ± 4.74%; P = 0.04). Podoplanin was upregulated in HIV+ vs. HIV- cases regardless of pregnancy and villi type. Irrespective of pregnancy type, podoplanin immunoexpression within exchange villi was different (P = 0.008) between the HIV+ and HIV- groups. Conclusion: Placental fluid homeostasis is maintained by a podoplanin reticular-like complex within conducting and exchange villi, being upregulated in HIV-positive pregnancies.


Assuntos
Infecções por HIV/complicações , Glicoproteínas de Membrana , Placenta/química , Pré-Eclâmpsia/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Adulto , Feminino , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Placenta/metabolismo , Gravidez , Adulto Jovem
6.
Cytokine ; 111: 255-264, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30199767

RESUMO

Zika virus (ZIKV) has caused substantial concern worldwide owing to its association with severe birth defects, such as microcephaly and other congenital malformations. Inflammasomes, i.e., multi-protein complexes that induce inflammation and pyroptosis, are predicted to contribute to the immune response to this flavivirus. Accordingly, in this study, the in situ inflammasome response was evaluated in fatal cases of ZIKV-linked microcephaly. Brain tissue samples were collected from eight babies, including four ZIKV-positive microcephalic neonates who died after birth and four flavivirus-negative neonatal controls who died of other causes and whose central nervous system (CNS) architecture was preserved. In the ZIKV-positive newborn/stillbirth babies, the major histopathological alterations included atrophy of the cortical layer, a predominance of mononuclear cell infiltration in the Virchow-Robin space, neuronal necrosis, vacuolization and neuronal degeneration, neuronophagy, and gliosis. An immunohistochemical analysis of tissues in the neural parenchyma showed significantly higher expression of the receptors NLRP1, NLRP3, and AIM2, cytokines IL-1ß, IL-18, and IL-33, and enzymes caspase 1, iNOS, and arginase 1 in ZIKV-positive microcephaly cases than in flavivirus-negative controls. These results suggest that inflammasome activation can aggravate the neuroinflammatory response and consequently increase CNS damage in neonates with fetal neural ZIKV infection and microcephaly.


Assuntos
Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Inflamassomos/fisiologia , Microcefalia/patologia , Microcefalia/virologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Sistema Nervoso Central/metabolismo , Citocinas/metabolismo , Feminino , Feto/metabolismo , Feto/virologia , Humanos , Recém-Nascido , Inflamassomos/metabolismo , Masculino , Microcefalia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia
7.
Curr Med Sci ; 38(4): 632-639, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128872

RESUMO

Increasing evidence has revealed that maternal cytomegalovirus (CMV) infection may be associated with neurodevelopmental disorders in offspring. Potential relevance between the placental inflammation and CMV-related autism has been reported by clinical observation. Meanwhile, abnormal expression of Toll-like receptor 2 (TLR2) and TLR4 in placenta of patients with chorioamnionitis was observed in multiple studies. IL-6 and IL-10 are two important maternal inflammatory mediators involved in neurodevelopmental disorders. To investigate whether murine CMV (MCMV) infection causes alterations in placental IL-6/10 and TLR2/4 levels, we analyzed the dynamic changes in gene expression of TLR2/4 and IL-6/10 in placentas following acute MCMV infection. Mouse model of acute MCMV infection during pregnancy was created, and pre-pregnant MCMV infected, lipopolysaccharide (LPS)-treated and uninfected mice were used as controls. At E13.5, E14.5 and E18.5, placentas and fetal brains were harvested and mRNA expression levels of placental TLR2/4 and IL-6/10 were analyzed. The results showed that after acute MCMV infection, the expression levels of placental TLR2/4 and IL-6 were elevated at E13.5, accompanied by obvious placental inflammation and reduction of placenta and fetal brain weights. However, LPS 50 µg/kg could decrease the EL-6 expression at E13.5 and E14.5. This suggests that acute MCMV infection during pregnancy could up-regulate the gene expression of TLR2/4 in placental trophoblasts and activate them to produce more proinflammatory cytokine IL-6. High dose of LPS stimulation (50 µg/kg) during pregnancy can lead to down-regulation of IL-6 levels in the late stage. Imbalance of IL-6 expression in placenta might be associated with the neurodevelopmental disorders in progeny.


Assuntos
Infecções por Herpesviridae/metabolismo , Placenta/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Feminino , Infecções por Herpesviridae/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Complicações Infecciosas na Gravidez/genética , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Regulação para Cima
8.
Ann Biomed Eng ; 46(12): 1963-1974, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30003503

RESUMO

Recent global epidemics of viral infection such as Zika virus (ZIKV) and associated birth defects from maternal-fetal viral transmission highlights the critical unmet need for experimental models that adequately recapitulates the biology of the human maternal-fetal interface and downstream fetal development. Herein, we report an in vitro biomimetic placenta-fetus model of the maternal-fetal interface and downstream fetal cells. Using a tissue engineering approach, we built a 3D model incorporating placental trophoblast and endothelial cells into an extracellular matrix environment and validated formation of the maternal-fetal interface. We utilized this model to study ZIKV exposure to the placenta and neural progenitor cells. Our results indicated ZIKV infects both trophoblast and endothelial cells, leading to a higher viral load exposed to fetal cells downstream of the barrier. Viral inhibition by chloroquine reduced the amount of virus both in the placenta and transmitted to fetal cells. A sustained downstream neural cell viability in contrast to significantly reduced viability in an acellular model indicates that the placenta sequesters ZIKV consistent with clinical observations. These findings suggest that the placenta can modulate ZIKV exposure-induced fetal damage. Moreover, such tissue models can enable rigorous assessment of potential therapeutics for maternal-fetal medicine.


Assuntos
Feto , Transmissão Vertical de Doença Infecciosa , Modelos Biológicos , Placenta , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus/metabolismo , Feminino , Feto/embriologia , Feto/patologia , Feto/virologia , Humanos , Placenta/metabolismo , Placenta/patologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Infecção por Zika virus/embriologia , Infecção por Zika virus/patologia , Infecção por Zika virus/transmissão
9.
PLoS One ; 13(7): e0198784, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30028852

RESUMO

BACKGROUND: In sub-Saharan Africa, HIV, syphilis, malaria and anaemia are leading preventable causes of adverse pregnancy outcomes. In Kenya, policy states women should be tested for all four conditions (malaria only if febrile) at first antenatal care (ANC) visit. In practice, while HIV screening is conducted, coverage of screening for the others is suboptimal and early pregnancy management of illnesses is compromised. This is particularly evident at rural dispensaries that lack laboratories and have parallel programmes for HIV, reproductive health and malaria, resulting in fractured and inadequate care for women. METHODS: A longitudinal eight-month implementation study integrating point-of-care diagnostic tests for the four conditions into routine ANC was conducted in seven purposively selected dispensaries in western Kenya. Testing proficiency of healthcare workers was observed at initial training and at three monthly intervals thereafter. Adoption of testing was compared using ANC register data 8.5 months before and eight months during the intervention. Fidelity to clinical management guidelines was determined by client exit interviews with success defined as ≥90% adherence. FINDINGS: For first ANC visits at baseline (n = 529), testing rates were unavailable for malaria, low for syphilis (4.3%) and anaemia (27.8%), and near universal for HIV (99%). During intervention, over 95% of first attendees (n = 586) completed four tests and of those tested positive, 70.6% received penicillin or erythromycin for syphilis, 65.5% and 48.3% received cotrimoxazole and antiretrovirals respectively for HIV, and 76.4% received artemether/lumefantrine, quinine or dihydroartemisinin-piperaquine correctly for malaria. Iron and folic supplements were given to nearly 90% of women but often at incorrect doses. CONCLUSIONS: Integrating point-of-care testing into ANC at dispensaries with established HIV testing programmes resulted in a significant increase in testing rates, without disturbing HIV testing rates. While more cases were detected and treated, treatment fidelity still requires strengthening and an integrated monitoring and evaluation system needs to be established.


Assuntos
Anemia/diagnóstico , Suplementos Nutricionais , Infecções por HIV/diagnóstico , Malária/diagnóstico , Complicações Hematológicas na Gravidez/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Sífilis/diagnóstico , Adulto , Anemia/tratamento farmacológico , Anemia/metabolismo , Antibacterianos/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Eritromicina/uso terapêutico , Feminino , Ácido Fólico/administração & dosagem , Fidelidade a Diretrizes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Pessoal de Saúde , Humanos , Ferro na Dieta/administração & dosagem , Quênia , Ensaio de Proficiência Laboratorial/estatística & dados numéricos , Estudos Longitudinais , Malária/tratamento farmacológico , Malária/metabolismo , Penicilinas/uso terapêutico , Testes Imediatos/estatística & dados numéricos , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/metabolismo , Cuidado Pré-Natal/estatística & dados numéricos , Quinina/uso terapêutico , Quinolinas/uso terapêutico , Sífilis/tratamento farmacológico , Sífilis/metabolismo , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
10.
Proc Natl Acad Sci U S A ; 115(27): 7117-7122, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29915057

RESUMO

Maternal Zika virus (ZIKV) infection during pregnancy is recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. It remains unclear how ZIKV accesses the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may be viral reservoirs. In contrast, the related dengue virus (DENV) does not elicit teratogenicity. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV and DENV for different induced pluripotent stem cell-derived human cells, with a particular focus on microglia-like cells. We show that ZIKV infected isogenic neural progenitors, astrocytes, and microglia-like cells (pMGLs), but was only cytotoxic to neural progenitors. Infected glial cells propagated ZIKV and maintained ZIKV load over time, leading to viral spread to susceptible cells. DENV triggered stronger immune responses and could be cleared by neural and glial cells more efficiently. pMGLs, when cocultured with neural spheroids, invaded the tissue and, when infected with ZIKV, initiated neural infection. Since microglia derive from primitive macrophages originating in proximity to the maternal vasculature, they may act as a viral reservoir for ZIKV and establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before angiogenesis in the brain rudiments. Our data are also consistent with ZIKV and DENV affecting the integrity of the blood-brain barrier, thus allowing infection of the brain later in life.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Infecção por Zika virus/metabolismo , Zika virus/metabolismo , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/virologia , Células-Tronco Neurais/patologia , Células-Tronco Neurais/virologia , Neuroglia/patologia , Neuroglia/virologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Infecção por Zika virus/patologia
11.
PLoS One ; 13(6): e0198842, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29879190

RESUMO

OBJECTIVE: To determine whether vitamin D-binding protein (VDBP) in cervicovaginal fluid (CVF) is independently predictive of intra-amniotic infection and imminent spontaneous preterm delivery (SPTD, delivery within 48 hours) in women with preterm labor with intact membranes (PTL) or preterm premature rupture of membranes (PPROM). METHOD: This was a single-center retrospective cohort study. CVF samples for VDBP assays were obtained along with serum C-reactive protein (CRP) levels immediately after amniocentesis in consecutive women with PTL (n = 148) or PPROM (n = 103) between 23.0 and 34.0 weeks of gestation. VDBP levels in CVF were determined by enzyme-linked immunosorbent assay kits. The primary outcome measures were intra-amniotic infection [defined as positive amniotic fluid (AF) culture] and SPTD within 48 hours after sampling. RESULTS: In the multivariable analysis, elevated VDBP levels in CVF samples of PTL women were significantly associated with intra-amniotic infection and imminent preterm delivery, even after adjusting for potential confounders (e.g., gestational age at sampling, parity, and serum CRP). However, these relationships were not found in women with PPROM. In women with PTL, the areas under receiver operating characteristic curves of CVF VDBP level for predicting intra-amniotic infection and imminent preterm delivery were 0.66 and 0.71, with cut-off values of 1.76 µg/mL (sensitivity of 64.3% and specificity of 78.4%) and 1.37 µg/mL (sensitivity of 65.4% and specificity of 72.6%), respectively. The CVF VDBP levels were significantly higher in women with PPROM than in those with PTL. CONCLUSIONS: VDBP in the CVF independently predicts intra-amniotic infection and imminent preterm delivery in women with PTL, whereas in women with PPROM, an elevated VDBP level in CVF is not associated with increased risks of these two outcome variables.


Assuntos
Infecções Bacterianas/metabolismo , Líquidos Corporais/metabolismo , Ruptura Prematura de Membranas Fetais/metabolismo , Trabalho de Parto Prematuro/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Proteína de Ligação a Vitamina D/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Valor Preditivo dos Testes , Gravidez , Estudos Retrospectivos
12.
Brain Behav Immun ; 73: 51-65, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29870753

RESUMO

Activation of the maternal immune system during pregnancy is a well-established risk factor for neuropsychiatric disease in the offspring, yet, the underlying mechanisms leading to altered brain function remain largely undefined. Microglia, the resident immune cells of the brain, are key to adequate development of the central nervous system (CNS), and are prime candidates to mediate maternal immune activation (MIA)-induced brain abnormalities. As such, the effects of MIA on the immunological phenotype of microglia has been widely investigated. However, contradicting results due to differences in read-out and methodological approaches impede final conclusions on MIA-induced microglial alterations. The aim of this review is to critically discuss the evidence for an activated microglial phenotype upon MIA.


Assuntos
Microglia/fisiologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Comportamento Animal/fisiologia , Encéfalo/imunologia , Modelos Animais de Doenças , Feminino , Sistema Imunitário/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mães , Transtornos do Neurodesenvolvimento/fisiopatologia , Poli I-C/farmacologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/metabolismo , Ratos
13.
Respir Res ; 19(1): 93, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29747649

RESUMO

BACKGROUND: Intrauterine infection/inflammation plays an important role in the development of lung injury and bronchopulmonary dysplasia (BPD) in preterm infants, While a multifactorial genesis is likely, mechanisms involved in BPD after intrauterine infection/inflammation are largely unknown. Recent studies have suggested microRNAs (miRNAs) are likely to play a role. Therefore, this study aimed to study the effects and mechanisms of intrauterine infection/inflammation on lung development, and to identify miRNAs related to lung injury and BPD. METHODS: An animal model of intrauterine infection/inflammation was established with pregnant SD rats endocervically inoculated with E.coli. The fetal and neonatal rats were observed at embryonic day (E) 17, 19, 21 and postnatal day (P) 1, 3, 7, 14, respectively. Body weight, lung weight, the expression levels of NLRP3, TNF-α, IL-lß, IL-6, VEGF, Collagen I, SP-A, SP-B and SP-C in the lung tissues of fetal and neonatal rats were measured. Expression profiles of 1218 kinds of miRNAs in the lungs of neonatal rats were detected by miRNA microarray technique. Target genes of the identified miRNAs were predicted through online software. RESULTS: Intrauterine infection/inflammation compromised not only weight development but also lung development of the fetal and neonatal rats. The results showed significantly increased expression of NLRP3, TNF-α, IL-1ß, IL-6, Collagen I, and significantly decreased expression of VEGF, SP-A, SP-B and SP-C in the fetal and neonatal rat lung tissues in intrauterine infection group compared to the control group at different observation time point (P < 0.05). Forty-three miRNAs with significant differential expression were identified. Possible target genes regulated by the identified miRNAs are very rich. CONCLUSIONS: Intrauterine infection/inflammation results in lung histological changes which are very similar to those observed in BPD. Possible mechanisms may include NLRP3 inflammasome activation followed by inflammatory cytokines expression up-regulated, inhibiting the expression of pulmonary surfactant proteins, interfering with lung interstitial development. There are many identified miRNAs which target a wide range of genes and may play an important role in the processes of lung injury and BPD.


Assuntos
Mediadores da Inflamação/metabolismo , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Feminino , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Tamanho do Órgão/fisiologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Ratos , Ratos Sprague-Dawley
14.
Cell Rep ; 23(5): 1424-1434, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29719255

RESUMO

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is generally benign in humans. However, an emergent strain of ZIKV has become widespread, causing severe pre- and post-natal neurological defects. There is now an urgent need for prophylactic and therapeutic agents. To address this, we investigated six human monoclonal antibodies with ZIKV epitope specificity and neutralizing activity in mouse models of ZIKV infection and microcephaly. A single intraperitoneal injection of these antibodies conveyed distinct levels of adult and in utero protection from ZIKV infection, which closely mirrored their respective in vitro neutralizing activities. One antibody, ZK2B10, showed the most potent neutralization activity, completely protected uninfected mice, and markedly reduced tissue pathology in infected mice. Thus, ZK2B10 is a promising candidate for the development of antibody-based interventions and informs the rational design of ZIKV vaccine.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/farmacologia , Embrião de Mamíferos/embriologia , Microcefalia/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Infecção por Zika virus/tratamento farmacológico , Zika virus/metabolismo , Animais , Modelos Animais de Doenças , Embrião de Mamíferos/patologia , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos ICR , Microcefalia/metabolismo , Microcefalia/patologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia
15.
PLoS Pathog ; 14(5): e1007094, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29847585

RESUMO

During pregnancy, the placenta protects the fetus against the maternal immune response, as well as bacterial and viral pathogens. Bacterial pathogens that have evolved specific mechanisms of breaching this barrier, such as Listeria monocytogenes, present a unique opportunity for learning how the placenta carries out its protective function. We previously identified the L. monocytogenes protein Internalin P (InlP) as a secreted virulence factor critical for placental infection. Here, we show that InlP, but not the highly similar L. monocytogenes internalin Lmo2027, binds to human afadin (encoded by AF-6), a protein associated with cell-cell junctions. A crystal structure of InlP reveals several unique features, including an extended leucine-rich repeat (LRR) domain with a distinctive Ca2+-binding site. Despite afadin's involvement in the formation of cell-cell junctions, MDCK epithelial cells expressing InlP displayed a decrease in the magnitude of the traction stresses they could exert on deformable substrates, similar to the decrease in traction exhibited by AF-6 knock-out MDCK cells. L. monocytogenes ΔinlP mutants were deficient in their ability to form actin-rich protrusions from the basal face of polarized epithelial monolayers, a necessary step in the crossing of such monolayers (transcytosis). A similar phenotype was observed for bacteria expressing an internal in-frame deletion in inlP (inlP ΔLRR5) that specifically disrupts its interaction with afadin. However, afadin deletion in the host cells did not rescue the transcytosis defect. We conclude that secreted InlP targets cytosolic afadin to specifically promote L. monocytogenes transcytosis across the basal face of epithelial monolayers, which may contribute to the crossing of the basement membrane during placental infection.


Assuntos
Proteínas de Bactérias/metabolismo , Membrana Basal/microbiologia , Listeria monocytogenes/patogenicidade , Proteínas dos Microfilamentos/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Animais , Feminino , Feto/microbiologia , Humanos , Listeriose/metabolismo , Proteínas de Membrana/metabolismo , Placenta/metabolismo , Placenta/microbiologia , Gravidez , Fatores de Virulência/metabolismo
16.
PLoS Pathog ; 14(4): e1006944, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29672607

RESUMO

Despite extensive genetic diversity of HIV-1 in chronic infection, a single or few maternal virus variants become the founders of an infant's infection. These transmitted/founder (T/F) variants are of particular interest, as a maternal or infant HIV vaccine should raise envelope (Env) specific IgG responses capable of blocking this group of viruses. However, the maternal or infant factors that contribute to selection of infant T/F viruses are not well understood. In this study, we amplified HIV-1 env genes by single genome amplification from 16 mother-infant transmitting pairs from the U.S. pre-antiretroviral era Women Infant Transmission Study (WITS). Infant T/F and representative maternal non-transmitted Env variants from plasma were identified and used to generate pseudoviruses for paired maternal plasma neutralization sensitivity analysis. Eighteen out of 21 (85%) infant T/F Env pseudoviruses were neutralization resistant to paired maternal plasma. Yet, all infant T/F viruses were neutralization sensitive to a panel of HIV-1 broadly neutralizing antibodies and variably sensitive to heterologous plasma neutralizing antibodies. Also, these infant T/F pseudoviruses were overall more neutralization resistant to paired maternal plasma in comparison to pseudoviruses from maternal non-transmitted variants (p = 0.012). Altogether, our findings suggest that autologous neutralization of circulating viruses by maternal plasma antibodies select for neutralization-resistant viruses that initiate peripartum transmission, raising the speculation that enhancement of this response at the end of pregnancy could further reduce infant HIV-1 infection risk.


Assuntos
Anticorpos Neutralizantes/imunologia , Infecções por HIV/transmissão , HIV-1/genética , Transmissão Vertical de Doença Infecciosa , Plasma/metabolismo , Complicações Infecciosas na Gravidez/etiologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Feminino , Variação Genética , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Lactente , Testes de Neutralização , Período Periparto , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
17.
Biomark Med ; 12(5): 517-534, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29697287

RESUMO

A key element in any diagnostic technique is the antigen (Ag), a biomarker, but this is usually a protein that has a function to the parasite. Some biological aspects of the Ags and of the Toxoplasma gondii can influence the effectiveness of the diagnosis, as well as the antibody isotype and the characteristics of the assay. A large number of papers have assessed different proteins to distinguish the phases of infection, but the 'indices of effectiveness' differ among reports. This work presents for the first time a summary of all the Ags that have been evaluated, with standardized measurements of sensitivity and specificity. These values were calculated with information presented in the papers on Ag evaluations to differentiate the infection phases.


Assuntos
Antígenos de Protozoários/metabolismo , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/metabolismo , Toxoplasmose/diagnóstico , Toxoplasmose/metabolismo , Doença Aguda , Feminino , Humanos , Gravidez , Padrões de Referência
18.
J Reprod Immunol ; 127: 16-18, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29656181

RESUMO

In HIV infection, increased adverse perinatal outcomes reported among HIV-associated pregnancies are not fully understood. Currently, microbial product translocation (MT) from a permeable mucosa is demonstrated as a driver of inflammation, and may contribute to preterm delivery in HIV. Here, our results showed that plasma LPS levels (a representative marker of MT) were increased in HIV-infected women in the first and second trimester. Progesterone levels were significantly decreased in HIV-infected subjects in the first trimester and second trimester. There were significant inverse correlations between plasma LPS and progesterone in the first and second trimester. These results suggested heightened systemic MT and decreased plasma progesterone levels in HIV-infected pregnant women may play a role in increased incidence of preterm delivery.


Assuntos
Translocação Bacteriana/genética , Infecções por HIV/microbiologia , HIV-1/fisiologia , Complicações Infecciosas na Gravidez/microbiologia , Nascimento Prematuro/microbiologia , Adulto , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Humanos , Incidência , Lipopolissacarídeos/imunologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/metabolismo , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/metabolismo , Progesterona/sangue , Risco , Estados Unidos/epidemiologia , Adulto Jovem
19.
Nat Commun ; 9(1): 263, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343712

RESUMO

Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.


Assuntos
Placenta/metabolismo , Circulação Placentária , Complicações Infecciosas na Gravidez/imunologia , Infecção por Zika virus/imunologia , Imunidade Adaptativa , Animais , Encéfalo/embriologia , Encéfalo/patologia , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal , Feto/patologia , Imunidade Inata , Macaca mulatta , Imagem por Ressonância Magnética , Oxigênio/metabolismo , Permeabilidade , Placenta/imunologia , Placenta/patologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/fisiopatologia , Carga Viral , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia , Infecção por Zika virus/fisiopatologia
20.
PLoS One ; 13(1): e0191236, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29351333

RESUMO

The primary strategy to avoid mother-to-child transmission of human immunodeficiency virus (HIV) through breastfeeding is administration of highly active antiretroviral therapy (HAART) to HIV-positive pregnant women. Because significant changes in the pharmacokinetics of antiretroviral (ARV) drugs occur during pregnancy, quantifying HAART and the viral load in breast milk in this population is essential. Here, we developed an analytical assay for the simultaneous quantification of four ARV drugs in breast milk using ultra-performance liquid chromatography coupled to tandem mass spectrometry. We validated this method following Mexican and international guidelines. ARV drugs. We extracted the ARV drugs from 200 µL samples of breast milk and detected these drugs in a triple quadrupole mass spectrometer with positive electrospray ionization. The validated concentration ranges (ng/mL) for zidovudine, lamivudine, lopinavir, and ritonavir were 12.5-750, 50-2500, 100-5000 and 5 to 250, respectively. Additionally, the absolute recovery percentages (and matrix effects) were 91.4 (8.39), 88.78 (28.75), 91.38 (11.77) and 89.78 (12.37), respectively. We determined that ARV drugs are stable for 24 h at 8°C and 24°C for 15 days at -80°C. This methodology had the capacity for simultaneous detection; separation; and accurate, precise quantification of ARV drugs in human breast milk samples according to Mexican standard laws and United States Food and Drug Administration guidelines.


Assuntos
Fármacos Anti-HIV/análise , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Leite Humano/química , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Fármacos Anti-HIV/normas , Aleitamento Materno , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Colostro/química , Feminino , Infecções por HIV/prevenção & controle , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lamivudina/análise , Lopinavir/análise , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Padrões de Referência , Reprodutibilidade dos Testes , Ritonavir/análise , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas , Adulto Jovem , Zidovudina/análise
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