Showing papers in "American Journal of Reproductive Immunology in 2015"

Viral infections during pregnancy.

Abstract: Viral infections during pregnancy have long been considered benign conditions with a few notable exceptions, such as herpes virus. The recent Ebola outbreak and other viral epidemics and pandemics show how pregnant women suffer worse outcomes (such as preterm labor and adverse fetal outcomes) than the general population and non-pregnant women. New knowledge about the ways the maternal-fetal interface and placenta interact with the maternal immune system may explain these findings. Once thought to be 'immunosuppressed', the pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus. When this protection is breached, as in a viral infection, this security is weakened and infection with other microorganisms can then propagate and lead to outcomes, such as preterm labor. In this manuscript, we review the major viral infections relevant to pregnancy and offer potential mechanisms for the associated adverse pregnancy outcomes.

Interleukin-10: a pleiotropic regulator in pregnancy.

Abstract: Pregnancy is a unique and well-choreographed physiological process that involves intricate interplay of inflammatory and anti-inflammatory milieu, hormonal changes, and cellular and molecular events at the maternal-fetal interface. IL-10 is a pregnancy compatible cytokine that plays a vital role in maintaining immune tolerance. A wide array of cell types including both immune and non-immune cells secret IL-10 in an autocrine and paracrine manner. IL-10 binds to a specific receptor complex and activates JAK-STAT and PI3K-Akt signaling pathways while inhibiting NF-κB signaling pathway. IL-10 exerts its anti-inflammatory effects mainly by decreasing pro-inflammatory cytokines such as IL-1, IL-6, IL-12, and TNF-α, by inducing heme oxygenase-1, and by inhibiting antigen presentation via blocking major histocompatibility complex (MHC) class II expression. Prior studies from our group and others have shown that IL-10 also functions as a potent protector against vascular dysfunction, and enhancement of IL-10 may serve as an immunotherapeutic intervention to treat adverse pregnancy outcomes. This review seeks to critically evaluate the archetypal functions of IL-10 as an immune suppressive factor as well as its novel functions as a vascular protector and modulator of endoplasmic reticulum (ER) stress and autophagy in the context of normal and adverse pregnancy outcomes.

Fetal sex-based differences in maternal hormones, angiogenic factors, and immune mediators during pregnancy and the postpartum period.

Abstract: Problem Several pregnancy complications have disparities based on the sex of the fetus It is unknown whether the sex of the fetus differentially alters the maternal immune milieu, potentially contributing to the observed differences Method of study Using maternal plasma collected during 38 uncomplicated pregnancies (19 males, 19 females), we compared levels of cytokines, sex hormones, and angiogenic factors throughout gestation and postpartum Results Male fetal sex was associated with higher levels of proinflammatory cytokines (G-CSF, IL-12p70, IL-21, and IL-33) and angiogenic factors (PlGF and VEGF-A) compared with female fetal sex at multiple timepoints Female fetal sex was associated with higher levels of regulatory cytokines (IL-5, IL-9, IL-17, and IL-25) IL-27 increased throughout pregnancy regardless of fetal sex There was no fetal sex-based difference in analyte concentrations at the postpartum measurement Conclusion Women carrying a male fetus exhibit a more proinflammatory/proangiogenic immune milieu than women carrying a female fetus

The Role of Macrophages in Promoting and Maintaining Homeostasis at the Fetal-Maternal Interface

Abstract: A successful pregnancy requires that the maternal immune system adapts properly to avoid rejection of the semi-allogeneic fetus without compromising the ability to protect the mother and the fetus against infections. In this review, we describe the role of decidual macrophages in creating a homeostatic environment at the fetal-maternal interface. We also discuss their role in pregnancy complications as well as future possibilities to modulate macrophage function therapeutically. Decidual macrophages are enriched at the fetal-maternal interface and play a major role in the regulation of inflammatory responses and the maintenance of a tolerant environment. Their function is, however, not restricted to immune tolerance, but extends to include functions such as the recognition and clearance of infections, the clearance of apoptotic debris, and tissue remodeling. Decidual macrophages seem to largely function as tissue-resident macrophages that are crucial for maintaining homeostasis and reproductive success.

Natural Killer Cells: Key Players in Endometriosis.

Abstract: Endometriosis affects more than 10% of women, causing significant pain and morbidity. It is also a significant cause of infertility. The aetiology of the disease remains an enigma, and the mechanisms responsible for the associated infertility are unclear. A role for immune cells in endometriosis has been postulated, with attention directed towards natural killer (NK) cells and macrophages. NK cells kill tumours and infected cells but also have roles in tissue remodelling in several organs including the uterus and are key to successful pregnancy. Here, we explore evidence (from peer-reviewed published articles) of phenotypic and functional abnormalities in NK cell subpopulations of women with endometriosis. It is clear that peripheral blood NK cells and peritoneal NK cells have reduced cytotoxic function in women with endometriosis. Uterine NK cells have a vital role in infertility, but very little research has been carried out in this area. We propose that abnormal u NK cell activity may contribute to the pathogenesis of endometriosis and its associated infertility and that future research should focus on this complex area.

Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios.

Abstract: Problem We evaluated the clinical efficacy of immunosuppressive treatment with tacrolimus for repeated implantation failure (RIF) patients who have elevated in T helper (Th1)/Th2 cytokine producing cell ratios. Method of study This was a prospective cohort study of treatment for RIF patients (n = 42) with elevated peripheral blood Th1 (CD4+/IFN-γ+)/Th2 (CD4+/IL-4+) cell ratios at the Sugiyama clinic between November 2011 and October 2013. Twenty-five patients were treated with tacrolimus (treatment group) and 17 received no treatment (control group). Treatment group received tacrolimus 2 days before embryo transfer and continued until the day of the pregnancy test, for a total of 16 days. The daily dose of tacrolimus (1–3 mg) was determined based on the degree of the Th1/Th2 cell ratio. Results The clinical pregnancy rate of the treatment group was 64.0%, which was significantly higher than that of the control group (0%) (P < 0.0001). In the treatment group, the miscarriage rate was 6.3%, the live birthrate was 60.0% (P < 0.0001). There was no significant side-effect from tacrolimus in treatment group. No one developed obstetrical complications during pregnancy. Conclusion An immunosuppressive treatment using tacrolimus improved pregnancy outcome of repeated implantation failure patients with elevated Th1/Th2 ratios.

Toll‐like Receptor‐Mediated Responses by Placental Hofbauer Cells (HBCs): A Potential Pro‐Inflammatory Role for Fetal M2 Macrophages

Abstract: Problem Microbial-driven responses in placenta are linked with adverse pregnancy outcomes. The role of Toll-like receptor (TLR) function in Hofbauer cells (HBCs) and fetal macrophages of the placental villous core remains understudied. Method of Study Flow cytometry and immunohistochemistry (IHC) were used to establish the phenotype of HBCs. Regulation of cytokine secretion in response to treatment with TLR agonists and expression levels of TLRs and co-activators were compared in HBCs, placental fibroblasts (FIBs), and human umbilical vein endothelial cells (HUVECs) using ELISA and qPCR. Results Although flow cytometry and IHC revealed HBCs to be M2 (anti-inflammatory) macrophages, LPS and polyinosinic: polycytidylic acid [poly (I:C)] treatments markedly enhanced IL-6 secretion by HBCs, and expression of TLR-2, TLR-3, TLR-4, CD14, and MD-2 was the highest in HBCs. Conclusion These results indicate that although HBCs are M2 macrophages, inflammatory responses are induced through TLR-3 and TLR-4 in this cell type, suggesting a role in microbial-driven placental/fetal inflammation.

Reduced Myeloid-derived Suppressor Cells in the Blood and Endometrium is Associated with Early Miscarriage.

Abstract: Problem The contribution of myeloid-derived suppressor cells (MDSC) in patients suffering from early or recurrent miscarriage is unknown. MDSC are implicated in modulation of T-cell response in healthy pregnancies; however, the role of MDSC in patients suffering from miscarriage has not been studied. We hypothesized that MDSC play major role in inducing maternal–fetal tolerance and this tolerance is compromised in patients suffering from miscarriage. Method of study MDSC level was assessed by flow cytometry and immunostaining in blood and endometrial decidua, respectively. Activation of T cells was determined by MTT proliferation and IL-2 ELISA assays. Results and Conclusion The miscarriage patients harbor reduced level of functionally suppressive MDSC in blood and endometrium as compared to healthy control women with successful pregnancies. These results suggest MDSC regulate maternal tolerance in healthy pregnancies and that drug inducing MDSC could have therapeutic implication in the miscarriage patients.

Subpopulations of macrophages within eutopic endometrium of endometriosis patients.

Abstract: Problem Endometriosis is recognized as a chronic inflammatory disease and is related to immune response. There have been reports that revealed the different distribution of macrophage within the eutopic endometrium of women with endometriosis. Macrophages are functionally polarized into M1 and M2 cell lineages. We studied a difference in the subpopulations of M1 and M2 macrophages within the eutopic endometrium in patients with or without endometriosis to investigate how the eutopic endometrium is stimulated immunologically. Method of study Thirty-six patients with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group) were analyzed. Paraffin-embedded endometrial specimens were used for the study. Consecutive sections were used for immunostaining of CD68 (pan-macrophage marker) and CD163 (M2 macrophage marker). Cells positive for each marker were quantified, and the ratio of M2 macrophages in pan-macrophages was calculated. Result The endometriosis group had a significantly higher number of pan-macrophages than the control group in all phases (P < 0.05). The ratios of M2 macrophages in pan-macrophages were significantly lower in all phases in the endometriosis group (P < 0.05). Conclusion The macrophage population slants toward M1 in the endometrium of endometriosis patients. The endometrium appeared to be stimulated by some organelles and/or substances that induce M1 in endometriosis patients.

Injectable progestin-only contraception is associated with increased levels of pro-inflammatory cytokines in the female genital tract

Abstract: PROBLEM: Genital inflammatory changes may be a mechanism of increased HIV risk among injectable progestin-only contraception (IPC) users. METHOD OF STUDY: We conducted a cross-sectional analysis of 376 Kenyan and South African women. Genital cytokines and secretory leukocyte peptidase inhibitor concentrations in a reference population were compared to IPC users and women with reproductive tract infections. RESULTS: No significant variability in marker concentrations was observed by age or site. Depot medroxyprogesterone acetate (DMPA) users had significantly higher MIP-1alpha MIP-1beta IL-6 IL-8 IP-10 and RANTES concentrations. Norethisterone oenanthate users had significantly higher IL-6 IL-8 and RANTES concentrations. Women with sexually transmitted infections had variable inflammation and women with bacterial vaginosis exhibited a mixed profile of up and downregulation. CONCLUSION: The finding of substantial mucosal inflammation among DMPA users provides evidence which combined with the results of prior studies suggests that DMPA may create an immune environment conducive to HIV target cell recruitment and inhibitory for antiviral activity. (c) 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Simultaneous Detection and Evaluation of Four Subsets of CD4+ T Lymphocyte in Lesions and Peripheral Blood in Endometriosis

Abstract: Problem The proportion of CD4+ T lymphocytes, Th1, Th2, Th17, and regulatory T cells in endometriosis lesions and peripheral blood are not known. Method of study Lymphocytes were isolated from endometriosis lesions (n = 10) and endometrium (n = 10). Lymphocytes in peripheral blood were isolated from patients with and without endometriosis (n = 10, 10). The CD4+ T-lymphocyte profile was analyzed by flow cytometry. Results The proportion of Th1 lymphocytes was significantly lower in endometriosis tissue (59.64 ± 9.2%) in comparison with endometrial tissue (79.07 ± 8.97%), whereas the Th17 lymphocyte fraction was significantly higher in endometriosis tissue (6.66 ± 2.53%) in comparison with endometrial tissue (2.27 ± 1.51%). Analysis of peripheral blood indicated that the Th1 proportion was significantly higher in women with endometriosis (10.25 ± 2.82%) in comparison with controls (6.96 ± 4.13%). Conclusion The CD4+ T-lymphocyte profile in lesions and peripheral blood is altered in women with endometriosis. These findings may help better understanding of T-lymphocyte involvement in the pathophysiology of endometriosis.

Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy.

Abstract: Pregnancy presents a great challenge to the maternal immune system. Given that maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to serve a central function in altering the maternal immune responses. Regulatory T cells (Tregs) and the PD-1/PD-L1 pathway are both critical in controlling the immune responses. Recent studies have proved the critical function of the PD-1/PD-L1 pathway in regulating the T-cell homeostasis and the peripheral tolerance through promoting the development and function of Tregs, and inhibiting the activation of effector T cells. The function of the PD-1/PD-L1 pathway in feto-maternal interface and pregnancy has been investigated in human and animal models of pregnancy. In this review, we provide recent insight into the role of the PD-1/PD-L1 pathway in regulating T-cell homeostasis, maternal tolerance, and pregnancy-related complications as well as its possible applicability in clinical immunotherapy.

Transcriptomic profiling of human choriodecidua during term labor: inflammation as a key driver of labor.

Abstract: PROBLEM: Inflammation is a driver of labor in myometrium and cervix; however, the involvement of decidua is poorly defined. We have reported decidual leukocyte infiltration prior to and during labor; the regulators of these inflammatory processes are unknown. METHOD OF STUDY: Choriodecidua RNA obtained after term labor or elective cesarean delivery was applied to Affymetrix GeneChips. Pathway analysis and gene validation were performed. RESULTS: Extensive inflammatory activation was identified in choriodecidua following labor, predominantly upregulation of genes regulating leukocyte trafficking and cytokine signalling. Genes governing cell fate, tissue remodelling, and translation were also altered. Upregulation of candidate genes (ICAM1, CXCR4, CD44, TLR4, SOCS3, BCL2A, and IDO) was confirmed. NF?B, STAT1&3, HMGB1, and miRNA-21, miRNA-46, miRNA-141, and miRNA-200 were predicted upstream regulators. CONCLUSION: This study confirms inflammatory processes are major players in labor events in choriodecidua, as in other gestational tissues. Suppressing uterine inflammation is likely to be critical for arresting premature labor.

Prevalence of Regulatory T-Cell Subtypes in Preeclampsia.

Abstract: Problem: The prevalence of regulatory T cells (Tregs) is lower in preeclampsia (PE) compared to healthy pregnancy (HP). However, the proportion of recently described Treg subtypes has not been investigated. Method: Peripheral blood samples of 19 PE and 21 HP women in the third trimester were evaluated using flow cytometry for the prevalence of activated T cells and naive, effector, thymic, extrathymic, and exhausted Tregs. Results: The prevalence of activated T cells and exhausted Tregs was higher in PE than in HP. The prevalence of the functionally most active effector Tregs is decreased, while naive Tregs appear to be unaffected in PE compared to HP. No difference was detected between Tregs according to their origin (thymic or extrathymic). Conclusion: The combination of lower effector Treg and higher exhausted Treg prevalence may account for the decrease in the functionality of Tregs in PE.

Uterine Spiral Artery Remodeling: The Role of Uterine Natural Killer Cells and Extravillous Trophoblasts in Normal and High-Risk Human Pregnancies.

Abstract: The process of uterine spiral artery remodeling in the first trimester of human pregnancy is an essential part of establishing adequate blood perfusion of the placenta that will allow optimal nutrient/waste exchange to meet fetal demands during later development. Key regulators of spiral artery remodeling are the uterine natural killer cells and the invasive extravillous trophoblasts. The functions of these cells as well as regulation of their activation states and temporal regulation of their localization within the uterine tissue are beginning to be known. In this review, we discuss the roles of these two cell lineages in arterial remodeling events, their interaction/influence on one another and the outcomes of altered temporal, and spatial regulation of these cells in pregnancy complications.

Glucose and metformin modulate human first trimester trophoblast function: a model and potential therapy for diabetes-associated uteroplacental insufficiency.

Abstract: Problem Diabetes confers an increased risk of preeclampsia, but its pathogenic role in preeclampsia is poorly understood. The objective of this study was to elucidate the effects of excess glucose on trophoblast function and whether any changes could be reversed by metformin. Method of study The human first trimester trophoblast cell line (Sw.71) was treated with glucose at 5, 10, 25, and 50 mm, in the presence and absence of metformin. Trophoblast migration was quantified and supernatant cytokine, chemokine, and angiogenic factors measured. Results Increasing concentrations of glucose significantly increased trophoblast secretion of the inflammatory cytokines/chemokines: IL-1β, IL-6, IL-8, GRO-α, RANTES, and G-CSF; significantly increased trophoblast secretion of the anti-angiogenic factors sFlt-1 and sEndoglin; and significantly decreased trophoblast migration. Excess glucose-induced trophoblast IL-1β production was inhibited by disabling the Nalp3/ASC inflammasome. Metformin partially reduced the glucose-induced inflammatory response, but had no effect on the anti-angiogenic or antimigratory response. Conclusion Excess glucose induced a pro-inflammatory, anti-angiogenic, and antimigratory state in first trimester trophoblast cells. Glucose-induced trophoblast IL-1β secretion was mediated by the inflammasome. Glucose-induced inflammation was partially reversed by metformin. These findings demonstrate the pleiotropic effects of hyperglycaemia on the trophoblast, providing potential explanations for the strong link between diabetes and preeclampsia.

Immune changes and dysphoric moods across the postpartum.

Abstract: Problem Little is known about postpartum immune recovery and relationships of common dysphoric moods, stress, immunology, and endocrinology. Method of study Healthy women (n = 72) were followed for six postpartum months with immune and hormone measures and dysphoric moods and stress scales. A panel of cytokines produced in mitogen-stimulated whole blood assays were measured at each time, along with plasma levels of hsC-reactive protein (hsCRP), Interleukin-6 (IL-6), and a panel of hormones. Results Cellular immunity, measured by production of Interferon-gamma (IFNγ) and (Interleukin-2 (IL-2) from stimulated whole blood culture, was low in the early postpartum with changes by 3 months. Tumor necrosis factor alpha (TNFα) showed a similar pattern. Plasma levels of CRP and Interleukin-6 (IL-6) showed higher levels in the early postpartum. Mood disturbance scores dropped across the postpartum with a change in slope at 3 months. No significant relationships were found between immune, endocrine, and psychosocial measures. Conclusion Return to normal cellular immune function may take 3–4 months in the postpartum. Some aspects of early immunology (hsCRP and IL-6) probably reflect the latter stage of pregnancy, the stress of birth and the inflammation associated with involution. Dysphoric moods are higher in the early postpartum but are not related to immune factors or hormones.

Microbes Central to Human Reproduction

Abstract: As studies uncover the breadth of microbes associated with human life, opportunities will emerge to manipulate and augment their functions in ways that improve health and longevity. From involvement in the complexities of reproduction and fetal/infant development, to delaying the onset of disease, and indeed countering many maladies, microbes offer hope for human well-being. Evidence is emerging to suggest that microbes may play a beneficial role in body sites traditionally viewed as being sterile. Although further evidence is required, we propose that much of medical dogma is about to change significantly through recognition and understanding of these hitherto unrecognized microbe–host interactions. A meeting of the International Scientific Association for Probiotics and Prebiotics held in Aberdeen, Scotland (June 2014), presented new views and challenged established concepts on the role of microbes in reproduction and health of the mother and infant. This article summarizes some of the main aspects of these discussions.

Placental Regulation of Inflammation and Hypoxia after TNF-α Infusion in Mice.

Abstract: Problem Increased levels of inflammatory cytokines are demonstrated in the serum of women with pre-eclampsia. TNF-α infusion in animal models induces proteinuric hypertension similar to human pre-eclampsia. The effect of TNF-α on regulation of the immune and hypoxic pathways in the developing placenta and their relationship with experimental pre-eclampsia remains unexamined. Method of Study TNF-α was infused into pregnant mice, and the effects on maternal hypertension, proteinuria, circulating levels of sFlt-1 and corresponding placental changes in molecules responding to inflammation (TLR-3 and TLR-4) and hypoxia (HIF-1α) were examined. Results TNF-α infusion resulted in maternal hypertension and proteinuria. Molecular changes in the placenta involved upregulation of TLR-3, TLR-4 and HIF-1α. Serum levels of sFlt-1 were high in pregnant animals, but not further upregulated by TNF-α infusion. Conclusion A role for maladaptive regulation of TLR and HIF-1α induced by an imbalance in inflammatory cytokines is implicated in the pathogenesis of pre-eclampsia.

GLP-1 Receptor Agonist Exenatide Attenuates the Detrimental Effects of Obesity on Inflammatory Profile in Testis and Sperm Quality in Mice

Abstract: Problem Male obesity has been linked to subfecundity. This study is to investigate the effects of GLP-1 receptor (GLP-1R) agonist exenatide on sperm quality in high-fat diet (HFD)-induced obese mice. Method of study After 12 weeks of chow diet (CD) or HFD challenge, mice on HFD were allocated to either saline or exenatide (24 nmol/kg/day) interventions for 8 weeks. Sperm quality and the inflammatory profile of testis were compared among three groups. Results Obesity reduced the quality of sperm and changed the inflammatory profile characterized by increased mRNA expression levels of TNF-α, MCP-1, and F4/80 in testis. Exenatide intervention reduced the expression of pro-inflammatory cytokines and improved the quality of sperm. Conclusion HFD-induced obesity leads to the impairment of sperm quality and increased inflammation of testis in mice, and the abnormal physiology can be attenuated by exenatide treatment. Exenatide treatment may bring additional profits to obese and diabetes men by improving sperm function.

Influence of Testosterone on Inflammatory Response in Testicular Cells and Expression of Transcription Factor Foxp3 in T Cells

Abstract: Problem Previous studies demonstrated a strong association between low androgen levels and reduced capacity to mount an inflammatory response. However, the mechanisms underlying these observations are largely not understood. Methods of study Generation of CD4+CD25+Foxp3+ regulatory T cells in Leydig cell-conditioned media was determined by flow cytometry and ELISA. Influence of testosterone on cytokine response was measured in LPS-stimulated testicular macrophages, Sertoli and peritubular cells. Results Leydig cell-conditioned media dose-dependently stimulated expression of transcription factor Foxp3 and secretion of IL-10 in splenic CD4+ T cells, an effect abolished by addition of the anti-androgen flutamide. In isolated Sertoli and peritubular cells, testosterone pre-treatment suppressed the LPS-induced inflammatory response on TNF-α mRNA expression, while no effect was evident in testicular macrophages (TM). Conclusions Androgens can influence the immune system under normal conditions by the generation and functional differentiation of regulatory T cells and in testicular inflammation by direct effect on Sertoli and peritubular cells.

Microorganisms in the Female Genital Tract during Pregnancy: Tolerance versus Pathogenesis

Abstract: Microorganisms in the pregnant female genital tract are not always associated with pathology. The factors that influence the maternal response to microorganisms remain ill defined. We review the state of knowledge of microbe-host interactions in gestational tissues and highlight mechanisms that promote tolerance or pathogenesis. Tolerance to microorganisms is promoted during pregnancy by several mechanisms including upregulation of anti-inflammatory mediators, induction of endotoxin tolerance, and possibly by regulation of autophagy. Conversely, an altered vaginal microbiota or a pre-existing viral presence may result in induction of excessive inflammation and preterm labor. Although infections play a prevalent role in preterm birth, microbes are present in gestational tissues of women with healthy outcomes and may provide beneficial functions. The complex interactions between different microbial species and the maternal immune system during gestation remain incompletely elucidated.

Accurate Prediction of the Stage of Histological Chorioamnionitis before Delivery by Amniotic Fluid IL-8 Level.

Abstract: Objective To estimate the stage of histological chorioamnionitis (h-CAM) antenatally using clinical data. Materials and methods Four hundred and twenty-eight singleton mothers were recruited. Clinical data including the levels of white blood cell count (WBC), C-reactive protein (CRP), amniotic fluid interleukin-8 (AF-IL-8) at Cesarean section, and maternal body temperature (MBT) were collected. Results Histological chorioamnionitis was present in 45.3% of the cases. Poor neonatal prognosis was highest (59.1%) in cases with h-CAM stage III. AF-IL-8 (odds ratio: 8.5, 95% CI: 5.1-14.8, P < 0.0001) and MBT (odds ratio: 2.3, 95% CI: 1.13–4.1, P = 0.0192) were independent risk factors for h-CAM. The cutoff value of AF-IL-8 for predicting each stage of h-CAM (stage I or higher, stage II or higher, and stage III) were ≥9.9 ng/mL, ≥17.3 ng/mL, and ≥55.9 ng/mL, respectively. Conclusion The stage of h-CAM was able to be predicted accurately by the level of AF-IL-8 before delivery.

Impact of CD4+ Lymphocytes and HIV Infection on Anti‐Müllerian Hormone Levels in a Large Cohort of HIV‐infected and HIV‐uninfected Women

Abstract: Problem Effects of HIV infection on ovarian function and aging are unclear. Method of study Anti-Mullerian Hormone (AMH) levels were analyzed in 2621 HIV-infected and 941 uninfected participants using left-censored longitudinal models. Results Age-adjusted AMH levels were 16% lower in women with undetectable viraemia and 26% lower in detectable viraemia, relative to uninfected women. Current CD4 count associated with higher AMH in both HIV-infected and HIV-uninfected women. After controlling for current and nadir CD4, AMH was ~15% higher in HIV-infected relative to uninfected women, regardless of HIV viraemia. Gravidity, amenorrhea, and nadir total lymphocyte counts associated with higher AMH; hormonal contraceptive use and past weight loss associated with lower AMH. Conclusions CD4 + lymphocyte counts were associated with AMH in both HIV-infected and uninfected women. After adjustment for CD4 counts and age, HIV infection was associated with higher AMH. CD4 T cells and cellular activation may influence ovarian granulosa cell function.

Effect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta-Analysis.

Abstract: The effects of prednisolone on pregnancy outcome are open to debate. This meta-analysis was performed to evaluate the efficiency of prednisolone administration on unexplained recurrent miscarriage (RM) and the process of assisted reproductive technology (ART). Relevant publications were searched from databases and the included randomized controlled trials (RCTs) investigated effects of prednisolone administration in women with unexplained RM or during ART. The outcomes in our analysis were measured in terms of risk ratios (RRs) with 95% confidence intervals (CI) using random effect models. This meta-analysis was performed based on pregnancy outcomes following prednisolone treatment. This meta-analysis provides evidence that prednisolone therapy improves pregnancy outcomes in women with idiopathic RM (live birth rate: RR 1.58, 95% CI 1.23-2.02; successful pregnancy outcome: RR 7.63, 95% CI 3.71-15.69; miscarriage rate: RR 0.42, 95% CI 0.28-0.61). Our meta-analysis revealed a non-significant effect of prednisolone on pregnancy outcome during intracytoplasmic sperm injection (ICSI) cycles (pregnancy rate: RR 1.02, 95% CI 0.84-1.24; clinical pregnancy rate: RR 1.01, 95% CI 0.82-1.24; implantation rate: RR 1.04, 95% CI 0.85-1.28). Prednisolone administration may improve pregnancy outcomes in women with idiopathic RM; its efficacy in women undergoing ICSI is not significant.

Systemic inflammation in the extremely low gestational age newborn following maternal genitourinary infections.

Abstract: Problem Gestational genitourinary infections are associated with life-long disabilities, but it is unknown if neonatal inflammation is involved.

Chemerin Expression in the Peritoneal Fluid, Serum, and Ovarian Endometrioma of Women with Endometriosis.

Abstract: Problem Inflammation is an essential process in the pathogenesis of endometriosis. Method of study Serum and peritoneal fluid (PF) samples were collected from women with endometriosis (n = 31) and women without endometriosis (n = 48). Chemerin, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels in serum and PF samples were determined with a specific enzyme-linked immunosorbent assay. Eutopic endometrial tissue from controls and ovarian endometriotic cysts were obtained during surgery. Expression of chemerin and chemerin receptors in ectopic and eutopic endometrial tissues was measured on real-time reverse transcriptase–polymerase chain reaction. Protein expression was examined with Western blot and densitometric analysis. Results Chemerin concentrations were higher in PF from women with endometriosis than that in that from controls. PF chemerin concentrations were significantly correlated with both TNF-α and IL-6 levels in PF. The mRNA and protein of chemerin and its receptor were significantly increased in the ovarian endometrioma tissue compared with eutopic endometrium of controls. Conclusion These findings suggest that chemerin plays a role in endometriosis-related pelvic inflammation.

Placenta Growth Factor Induces Invasion and Activates p70 during Rapamycin Treatment in Trophoblast Cells

Abstract: Problem Aberrant trophoblast invasion has been associated with human intrauterine growth restriction (IUGR) and preeclampsia (PE). Our objective was to determine placenta growth factor (PlGF)-mediated regulation of cell invasion in trophoblast cells with reduced mammalian target of Rapamycin (mTOR) signaling. Method of study First trimester SW 71 trophoblast cells were subjected to invasion assays with the following conditions: 10% FBS, 10% FBS with Rapamycin, and 10% FBS with Rapamycin and PlGF. mTOR siRNA was also done in these cells. Western blots were performed on cell lysates with antibodies against phospho- and total mTOR, 70-kDa ribosomal protein kinase I (p70), 4EBP1, extracellular regulated kinase (ERK), and phosphatidylinositol-3 kinase (AKT). Results Compared to controls, trophoblast cells showed: (i) a 33% decrease in invasion following Rapamycin treatment, (ii) protection from decreased invasion following Rapamycin and PlGF treatment, (iii) a 31% decrease in mTOR phosphorylation with Rapamycin, (iv) increased phosphorylation of p70 (43%) with Rapamycin and PlGF, and (v) a 76% decrease in invasion following mTOR depletion. Conclusion We conclude that first trimester trophoblast invasion is functionally decreased when phosphorylation of mTOR is prevented and this decrease is recovered with the addition of PlGF. Mechanistically, this recovery involves the phosphorylation of p70 independent of mTOR.

Environmental Pollutant Polybrominated Diphenyl Ether, a Flame Retardant, Induces Primary Amnion Cell Senescence.

Abstract: OBJECTIVE: Polybrominated diphenyl ethers (PBDEs) are documented to increase the risk for spontaneous preterm birth (PTB) We hypothesize that PBDEs cause oxidative stress (OS) that leads to fetal cell senescence and inflammation associated with PTB METHODS: Primary amnion epithelial cells (n = 5) isolated from term, not in labor pregnancies, were exposed to PBDE congeners 47 and 99 (each 5 μm) ROS kinetics was monitored Morphologic changes, phospho-p38 MAPK (P-p38) activation, development of senescence, and induction of uterotonins (COX-2 expression) were quantified using light microscopy, Western blot, senescence-associated β-galactosidase (SA β-gal) staining, and qRT-PCR, respectively, after 48 and 72 hr of exposure RESULTS: Both PBDE congeners induced ROS within 2 min compared to controls (P CONCLUSIONS: Congener-dependent OS response, p38 MAPK activation, senescence, and COX-2 expression were seen in human amnion cells by PBDEs These findings demonstrate environment pollutant-induced senescence activation and inflammation can lead to pathways resulting in PTB Language: en

Clinical significance of inactivated glycogen synthase kinase 3β in HPV-associated cervical cancer: Relationship with Wnt/β-catenin pathway activation.

Abstract: Problem To determine the role of inactivated GSK3β with respect to Wnt/β-catenin pathway activation in HPV-16/18-associated cervical cancer. Method of study The expression of active (pGSK3β-Try216), inactive (pGSK3β-Ser9), and c-Myc as well as HPV-16/18 infection was analyzed in cervical intra-epithelial neoplasia (CIN), squamous cell carcinoma (SCCs) and normal by immunohistochemistry and multiplex PCR. The proteins level was also compared with β-catenin and APC expression. Results The dramatic decrease of pGSK3β-Try216 expression but ectopic overexpression of pGSK3β-Ser9 and c-Myc was observed both in CIN and SCCs samples compared to normal tissues. 57/67 CIN and 132/153 SCCs showed HPV-16 infection, while 3/67 CIN and 4/153 SCCs were harbored with HPV-18 infection. Both the proteins were significantly upregulated in HPV-16 infected cases (P = 0.0001; P = 0.001) and also positively correlated with nuclear β-catenin (P = 0.0001; P = 0.0001). Conclusion The process of generation of HPV-16-associated cervical tumorigenesis is synergized with GSK3β inactivation and overactivation of Wnt/β-catenin pathway.