Mucosal Integrity and Inflammatory Markers in the Female Lower Genital Tract as Potential Screening Tools for Vaginal Microbicides

Background—In the female genital tract, vaginal colposcopy, endometrial mucosal integrity and inflammatory mediators are potential in vivo biomarkers of microbicide and contraceptive safety. Study Design—A randomized, blinded crossover trial of 18 subjects comparing effects of Gynol II (putative inflammatory gel), HEC (putative inert gel) and no gel exposure on endometrial and vaginal epithelial integrity and endometrial and vaginal inflammatory markers (IL-1β, IL-6, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α, IL-1RA, IL-10, SLPI). Results—Gynol II was associated with more vaginal lesions. No endometrial disruptions were observed across conditions. In the vagina, RANTES (p=0.055) and IL-6 (p=0.04) were higher after HEC exposure than at baseline. In the endometrium, IL-1β (p=0.003) and IL-8 (p=0.025) were lower after Gynol II cycles than after no gel. Conclusions—Gynol II and HEC may modulate inflammatory markers in the vagina and endometrium. How these changes relate to infection susceptibility warrants further study

Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women

Background Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. Objective We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. Study Design Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days’ and 22 weeks 6 days’ gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. Results Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. Conclusion In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies

Intrauterine Growth Restriction Is a Direct Consequence of Localized Maternal Uropathogenic Escherichia coli Cystitis

Despite the continually increasing rates of adverse perinatal outcomes across the globe, the molecular mechanisms that underlie adverse perinatal outcomes are not completely understood. Clinical studies report that 10% of pregnant women will experience a urinary tract infection (UTI) and there is an association of UTIs with adverse perinatal outcomes. We introduced bacterial cystitis into successfully outbred female mice at gestational day 14 to follow pregnancy outcomes and immunological responses to determine the mechanisms that underlie UTI-mediated adverse outcomes. Outbred fetuses from mothers experiencing localized cystitis displayed intrauterine growth restriction (20–80%) as early as 48 hours post-infection and throughout the remainder of normal gestation. Robust infiltration of cellular innate immune effectors was observed in the uteroplacental tissue following introduction of UTI despite absence of viable bacteria. The magnitude of serum proinflammatory cytokines is elevated in the maternal serum during UTI. This study demonstrates that a localized infection can dramatically impact the immunological status as well as the function of non-infected distal organs and tissues. This model can be used as a platform to determine the mechanism(s) by which proinflammatory changes occur between non-contiguous genitourinary organ

Global report on preterm birth and stillbirth (2 of 7): discovery science

<p>Abstract</p> <p>Background</p> <p>Normal and abnormal processes of pregnancy and childbirth are poorly understood. This second article in a global report explains what is known about the etiologies of preterm births and stillbirths and identifies critical gaps in knowledge. Two important concepts emerge: the continuum of pregnancy, beginning at implantation and ending with uterine involution following birth; and the multifactorial etiologies of preterm birth and stillbirth. Improved tools and data will enable discovery scientists to identify causal pathways and cost-effective interventions.</p> <p>Pregnancy and parturition continuum</p> <p>The biological process of pregnancy and childbirth begins with implantation and, after birth, ends with the return of the uterus to its previous state. The majority of pregnancy is characterized by rapid uterine and fetal growth without contractions. Yet most research has addressed only uterine stimulation (labor) that accounts for <0.5% of pregnancy.</p> <p>Etiologies</p> <p>The etiologies of preterm birth and stillbirth differ by gestational age, genetics, and environmental factors. Approximately 30% of all preterm births are indicated for either maternal or fetal complications, such as maternal illness or fetal growth restriction. Commonly recognized pathways leading to preterm birth occur most often during the gestational ages indicated: (1) inflammation caused by infection (22-32 weeks); (2) decidual hemorrhage caused by uteroplacental thrombosis (early or late preterm birth); (3) stress (32-36 weeks); and (4) uterine overdistention, often caused by multiple fetuses (32-36 weeks). Other contributors include cervical insufficiency, smoking, and systemic infections. Many stillbirths have similar causes and mechanisms. About two-thirds of late fetal deaths occur during the antepartum period; the other third occur during childbirth. Intrapartum asphyxia is a leading cause of stillbirths in low- and middle-income countries.</p> <p>Recommendations</p> <p>Utilizing new systems biology tools, opportunities now exist for researchers to investigate various pathways important to normal and abnormal pregnancies. Improved access to quality data and biological specimens are critical to advancing discovery science. Phenotypes, standardized definitions, and uniform criteria for assessing preterm birth and stillbirth outcomes are other immediate research needs.</p> <p>Conclusion</p> <p>Preterm birth and stillbirth have multifactorial etiologies. More resources must be directed toward accelerating our understanding of these complex processes, and identifying upstream and cost-effective solutions that will improve these pregnancy outcomes.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid, fetal and neonatal brain in the mouse

<div><p>Introduction</p><p>Exposure to prenatal inflammation is associated with diverse adverse neurobehavioral outcomes in exposed offspring. The mechanism by which inflammation negatively impacts the developing brain is poorly understood. Metabolomic profiling provides an opportunity to identify specific metabolites, and novel pathways, which may reveal mechanisms by which exposure to intrauterine inflammation promotes fetal and neonatal brain injury. Therefore, we investigated whether exposure to intrauterine inflammation altered the metabolome of the amniotic fluid, fetal and neonatal brain. Additionally, we explored whether changes in the metabolomic profile from exposure to prenatal inflammation occurs in a sex-specific manner in the neonatal brain.</p><p>Methods</p><p>CD-1, timed pregnant mice received an intrauterine injection of lipopolysaccharide (50 μg/dam) or saline on embryonic day 15. Six and 48 hours later mice were sacrificed and amniotic fluid, and fetal brains were collected (n = 8/group). Postnatal brains were collected on day of life 1 (n = 6/group/sex). Global biochemical profiles were determined using ultra performance liquid chromatography/tandem mass spectrometry (Metabolon Inc.). Statistical analyses were performed by comparing samples from lipopolysaccharide and saline treated animals at each time point. For the P1 brains, analyses were stratified by sex.</p><p>Results/Conclusions</p><p>Exposure to intrauterine inflammation induced unique, temporally regulated changes in the metabolic profiles of amniotic fluid, fetal brain and postnatal brain. Six hours after exposure to intrauterine inflammation, the amniotic fluid and the fetal brain metabolomes were dramatically altered with significant enhancements of amino acid and purine metabolites. The amniotic fluid had enhanced levels of several members of the (hypo) xanthine pathway and this compound was validated as a potential biomarker. By 48 hours, the number of altered biochemicals in both the fetal brain and the amniotic fluid had declined, yet unique profiles existed. Neonatal pups exposed to intrauterine inflammation have significant alterations in their lipid metabolites, in particular, fatty acids. These sex-specific metabolic changes within the newborn brain offer an explanation regarding the sexual dimorphism of certain psychiatric and neurobehavioral disorders associated with exposure to prenatal inflammation.</p></div

Bulletin mensuel de statistique / Institut national de la statistique et des études économiques...

novembre 19901990/11 (N11)

Amino acid metabolites altered in amniotic fluid, 6 hours after exposure to prenatal inflammation.

<p>Amino acid metabolites altered in amniotic fluid, 6 hours after exposure to prenatal inflammation.</p