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ABSTRACT: In this study, we sought to assess how essential activation of toll-like receptor 4 (TLR-4) is to fetal brain injury from intrauterine inflammation. Both wild-type and TLR-4 mutant fetal central nervous system cells were exposed to inflammation using lipopolysaccharide in vivo or in vitro. Inflammation could not induce neuronal injury in the absence of glial cells, in either wild-type or TLR-4 mutant neurons. However, injured neurons could induce injury in other neurons regardless of TLR-4 competency. Our results indicate that initiation of neuronal injury is a TLR-4-dependent event, while propagation is a TLR-4-independent event.
Reproductive sciences (Thousand Oaks, Calif.) 08/2012; 19(8):839-50. · 2.31 Impact Factor
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ABSTRACT: Maternal fever and/or chorioamnionitis at term are associated with an increased prevalence of adverse neurobehavioral outcomes in exposed offspring. Since the mechanisms of such injury are currently unknown, the objectives of this study were to elucidate whether intrauterine inflammation at term results in fetal brain injury. Specifically, we assessed brain injury by investigating the cytokine response, white matter damage, and neuronal injury and viability. A mouse model of intrauterine inflammation at term was utilized by injecting lipopolysaccharide (LPS), or normal saline into uterine horn. Compared to saline-exposed, LPS-exposed fetal brains had significantly increased IL-1β and IL-6 messenger RNA (mRNA) expression (P < .05 for both) and IL-6 protein levels by enzyme-linked immunosorbent assay (ELISA; P < 0.05). Fetal neurons were affected by the intrauterine and fetal brain inflammation, as demonstrated by significantly decreased microtubule-associated protein 2 (MAP2) mRNA expression and a decrease in immunocytochemical staining (a marker of neuronal cytoskeleton development; P < .05), altered neuronal morphology (P < 0.05), and delayed neurotoxicity (P < .05). These fetal neuronal changes occurred without overt changes in white matter damage markers. Marker of astrocyte development and astrogliosis (glial fibrillary acidic protein [GFAP]) did not show an increase; pro-oligodendrocyte marker (PLP1/DM20) was not significantly changed (P > .05). These studies may provide a critical mechanism for the observed long-term adverse neurobehavioral outcomes after exposure to chorioamnionitis at term.
Reproductive sciences (Thousand Oaks, Calif.) 03/2011; 18(9):900-7. · 2.31 Impact Factor
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ABSTRACT: The purpose of this study was to investigate whether magnesium sulfate (MgSO(4)) prevents fetal brain injury in inflammation-associated preterm birth (PTB).
In a mouse model of PTB, mice exposed to lipopolysaccharide (LPS) or normal saline (NS) by intrauterine injection were randomized to intraperitoneal treatment with MgSO(4) or NS [corrected]. From the 4 treatment groups (NS + NS; LPS + NS; LPS + MgSO(4); and NS + MgSO(4)), fetal brains were collected for quantitative polymerase chain reaction studies and primary neuronal cultures. Messenger RNA expression of cytokines, cell death, and markers of neuronal and glial differentiation were assessed. Immunocytochemistry and confocal microscopy were performed.
There was no difference between the LPS + NS and LPS + MgSO(4) groups in the expression of proinflammatory cytokines, cell death markers, and markers of prooligodendrocyte and astrocyte development (P > .05 for all). Neuronal cultures from the LPS + NS group demonstrated morphologic changes; this neuronal injury was prevented by MgSO(4) (P < .001).
Amelioration of neuronal injury in inflammation-associated PTB may be a key mechanism by which MgSO(4) prevents cerebral palsy.
American journal of obstetrics and gynecology 03/2010; 202(3):292.e1-9. · 3.28 Impact Factor
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ABSTRACT: Adverse neurological outcome is a major cause of long-term morbidity in ex-preterm children. To investigate the effect of parturition and inflammation on the fetal brain, we utilized two in vivo mouse models of preterm birth. To mimic the most common human scenario of preterm birth, we used a mouse model of intrauterine inflammation by intrauterine infusion of lipopolysaccharide (LPS). To investigate the effect of parturition on the immature fetal brain, in the absence of inflammation, we used a non-infectious model of preterm birth by administering RU486. Pro-inflammatory cytokines (IL-10, IL-1beta, IL-6 and TNF-alpha) in amniotic fluid and inflammatory biomarkers in maternal serum and amniotic fluid were compared between the two models using ELISA. Pro-inflammatory cytokine expression was evaluated in the whole fetal brains from the two models. Primary neuronal cultures from the fetal cortex were established from the different models and controls in order to compare the neuronal morphology. Only the intrauterine inflammation model resulted in an elevation of inflammatory biomarkers in the maternal serum and amniotic fluid. Exposure to inflammation-induced preterm birth, but not non-infectious preterm birth, also resulted in an increase in cytokine mRNA in whole fetal brain and in disrupted fetal neuronal morphology. In particular, Microtubule-associated protein 2 (MAP2) staining was decreased and the number of dendrites was reduced (P < 0.001, ANOVA between groups). These results suggest that inflammation-induced preterm birth and not the process of preterm birth may result in neuroinflammation and alter fetal neuronal morphology.
Journal of Neuroscience Research 02/2010; 88(9):1872-81. · 2.74 Impact Factor
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ABSTRACT: The purpose of this study was to elucidate possible mechanisms of fetal neuronal injury in inflammation-induced preterm birth.
With the use of a mouse model of preterm birth, the following primary cultures were prepared from fetal brains: (1) control neurons (CNs), (2) lipopolysaccharide-exposed neurons (LNs), (3) control coculture (CCC) that consisted of neurons and glia, and (4) lipopolysaccharide-exposed coculture (LCC) that consisted of lipopolysaccharide-exposed neurons and glia. CNs and LNs were treated with culture media from CN, LN, CCC, and LCC after 24 hours in vitro. Immunocytochemistry was performed for culture characterization and neuronal morphologic evidence. Quantitative polymerase chain reaction was performed for neuronal differentiation marker, microtubule-associated protein 2, and for cell death mediators, caspases 1, 3, and 9.
Lipopolysaccharide exposure in vivo did not influence neuronal or glial content in cocultures but decreased the expression of microtubule-associated protein 2 in LNs. Media from LNs and LCCs induced morphologic changes in control neurons that were comparable with LNs. The neuronal damage caused by in vivo exposure (LNs) could not be reversed by media from control groups.
Lipopolysaccharide-induced preterm birth may be responsible for irreversible neuronal injury.
American journal of obstetrics and gynecology 10/2009; 201(3):279.e1-8. · 3.28 Impact Factor
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ABSTRACT: Several published formulas exist for the determination of estimated fetal weight (EFW), with limited data on their comparative accuracies. The aims of our study were to assess and compare the performance of different EFW formulas in predicting actual birth weight (BW) in an urban population.
Patients with an EFW determined within 7 days of delivery were considered eligible for the study. Fourteen published formulas, derived from populations comparable to ours, were used to recalculate EFWs from the same initial measurements. The accuracy of the EFWs obtained from the different formulas were compared by percentage error methods using bias and precision and Bland-Altman limits of agreement methods. Sensitivity and specificity for prediction of being small for gestational age (SGA) were calculated.
Eighty-one fetuses were included in the study. Formula C of Hadlock et al [Hadlock C; log(10) BW = 1.335 - 0.0034(abdominal circumference [AC])(femur length [FL]) + 0.0316(biparietal diameter) + 0.0457(AC) + 0.1623(FL); Am J Obstet Gynecol 1985; 151:333-337] had the best performance according to the bias and precision method. Bland-Altman limits of agreement confirmed these results. Among the formulas, the sensitivity for detection of SGA ranged from 72% to 100%, and specificity was 41% to 88%. Hadlock C had the optimal sensitivity/specificity trade-off for detection of SGA.
Fourteen formulas showed considerable variation of bias and precision in our population as well as a wide range of sensitivities and specificities for SGA. The choice of the appropriate formula for EFW in a given population should be based on objective and explicit criteria. Consideration of bias and precision for the formula in the population being assessed is critical and may affect clinical care.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 09/2009; 28(8):1019-24. · 1.25 Impact Factor
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ABSTRACT: Maternal morbidity and/or mortality (MM) is increased in pyelonephritis and influenza. Alterations in the immune response could account for the increase MM. We sought to determine whether the immune response is functionally different during pregnant and nonpregnant (NP) states.
Mouse model of systemic and localized inflammation was used. Maternal serum was assessed for expression of T-helper cell type 1 and 2 cytokines. Maternal spleens were harvested for immunohistochemistry.
Systemic administration of lipopolysaccharides resulted in no mortality to NP mice compared with 88% in preterm and 100% in term mice. A potent cytokine response was present in both NP and pregnancy. Systemic inflammation in pregnancy results in increased CD8 and CD11c expression in spleens.
Differences in cytokine response to systemic inflammation is unlikley to modulate the increased MM during pregnancy. Altered T-cell and dendritic cell responses in pregnancy may be responsible for the increase in MM.
American journal of obstetrics and gynecology 05/2009; 200(4):430.e1-8. · 3.28 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether current attitudes regarding the use of progesterone to prevent preterm birth have changed since our last survey in 2003.
We mailed a 20 question survey to 1264 board certified Maternal-Fetal Medicine specialists in the United States between February and March of 2005 asking about their use and attitudes regarding progesterone to prevent preterm birth.
Five hundred and seventy-two surveys were returned (response rate of 45%). In 2005, 67% of respondents used progesterone to prevent SPTB, compared to 38% in 2003 (P < .001). Among users, 38% recommended progesterone for indications other than previous SPTB. Users were more concerned about lack of insurance coverage compared to nonusers but nonusers were more concerned about safety, efficacy, need for more data, and long-term neonatal effects.
Although the use of progesterone to prevent PTB has increased significantly since our last survey, there remain a substantial number of nonusers. Among users, many are using it for indications not yet proven in clinical trials. Current nonusers have higher levels of concerns compared to nonusers in the first survey and their major concern is the need for more data.
American journal of obstetrics and gynecology 11/2006; 195(4):1174-9. · 3.28 Impact Factor
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ABSTRACT: To characterize and assess the prevalence of chronic gynecologic pain and, more specifically, chronic vulvar pain.
A questionnaire was mailed to women aged 18-80 years who were ambulatory patients at an academic multidisciplinary practice. Quality of life, health history, obstetric and gynecologic history, and pain symptoms were assessed.
Of the 4,872 surveys mailed to deliverable addresses, 36.8% were returned. The population was primarily Caucasian (83%), with an average age of 50.2 years. Approximately 4% of respondents reported a history of vulvar pain in the 6 months preceding the survey, and 17% reported other types of chronic gynecologic pain. Women reporting vulvar and nonvulvar pain were 2 times as likely as asymptomatic women to report a history of depression and vaginal infections, a poorer quality of life (p < 0.001) and greater stress. Dyspareunia and pain with daily activities were reported more frequently by women with vulvar pain than by women with non-vulvar gynecologic pain.
The prevalence of vulvar pain in this study was lower than previously reported. Chronic gynecologic pain, and vulvar pain in particular, affects quality of life on both intimate and social levels. Self-reported stress and vaginal infections were the strongest correlates of chronic vulvar pain.
The Journal of reproductive medicine 01/2006; 51(1):3-9. · 0.87 Impact Factor
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ABSTRACT: A premenopausal 45-year-old woman underwent uterine artery embolization for suspected symptomatic leiomyomata. Fourteen months later, with renewed symptoms and a new pelvic mass, metastatic leiomyosarcoma was diagnosed. A lack of clinical response to a technically successful embolization should alert care providers that further evaluation and/or therapy is needed.
American Journal of Obstetrics and Gynecology 12/2004; 191(5):1733-5. · 3.47 Impact Factor
