Use of Remifentanil Associated with Lidocaine for Feticides in Late Terminations of Pregnancy: A Randomized Clinical Trial

<b><i>Introduction:</i></b> In France, performance of a termination of pregnancy is legally possible without any gestational age limit. After 22 weeks of gestation, a feticide is ethically performed using usually sufentanil and lidocaine. The aim of this study was to compare the use of remifentanil, a fast-acting morphine-derivating product, instead of sufentanil. <b><i>Methods:</i></b> This 2-center randomized, controlled, single-blinded phase-III treatment trial had 2 parallel arms: an experimental group using remifentanil with lidocaine versus a control group receiving sufentanil associated with lidocaine. This trial took place over a 40-month period. The primary outcome was time to fetal asystole after lidocaine injection. The secondary outcome measures were the procedure’s success rate, the rate of serious maternal side effects, and the presence of cellular or tissue modifications. <b><i>Results:</i></b> The study included 66 women, randomized into 2 groups of similar size and characteristics. Time to fetal asystole did not differ significantly between the groups, with a delay of 4 min (Q1−Q3, 2–11) in the sufentanil group and 4 min (Q1−Q3, 1–10) in the remifentanil group (<i>p</i> = 0.84). Similarly, the success rate of the procedure did not differ significantly. Fetal asystole was procured in &#x3c;2 min and persisted &#x3e;1 min for 16 (25.8%) women in our total population: 7 (22.5%) in the sufentanil group and 9 (29.0%) in the remifentanil group, <i>p</i> = 0.77. No severe maternal side effects were observed. Among the 49 fetopathological examinations performed, the few tissue and cell modifications observed did not cause any interpretation difficulties in either group. <b><i>Discussion/Conclusion:</i></b> Use of remifentanil instead of sufentanil for feticide procedure did not improve time to fetal asystole. No harmful effect was observed for either maternal tolerance or interpretation of the histologic slides.

Evaluation of the ultradiluted medication MPD 30 CH in the offspring of mice mothers treated with methylphenidate during lactation.

Background: Methylphenidate (MPD) is a non-stimulating amphetamine that has being used for some time in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and, in adequate doses, it promotes the remission of symptoms and the improvement of important aspects, as social interaction and academic performance1, in patients with ADHD. Literature data indicates that MPD attenuates maternal behavior in mices2. According to this line of study, the work “Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood”3 was carried out and confirmed that MPD administration during early lactation disrupts maternal behavior and causes anxiety in pups in adulthood. Would it be possible that ultradiluted and dynamized MPD change pups’ behavior? Objective: The aim of this study was to evaluate how the ultradiluted drug may or may not change the behavior of the animals at issue. Material and Methods: The medication was prepared according to the Brazilian Homeopathic Pharmacopeia, in the 30 CH dilution. The present study was approved by the Ethics Committee for Animal Experimentation of the Paulista University (No. 256/14 CEP / ICS / UNIP). Animals in this study were the same of the study above mentioned, and already published. Adult male mice were grouped among 13 animals of the experimental group (adults, offspring of mothers that received MPD during pregnancy) and 9 animals from the mother-control group, which did not take MPD during pregnancy. The 22 animals took ultradiluted MPD 30 CH medication in their drinking water ad libitum, for 20 days. In each water drinker, 5 drops of medication were added and stirred. Behavioral tests, such as the Open Field and the Light Dark Transition Test for mice, were performed. Data was analyzed statistically by the Student's T-Test to compare parametric data from two groups and the Mann-Whitney Test for nonparametric data, where p ≤ 0.05 is considered significant. Results and Discussion: In the Open Field Test, from the group of mothers medicated with methylphenidate during pregnancy, before the medication MPD 30 CH, animals showed a lower mobility and a greater immobility (p≤ 0.05) compared to the control-animals; after medication with the MPD 30 CH, animals exhibited an increase in mobility and a decrease in immobility, leading to no statistical difference between the medication group and the control group. In the Light Dark Transition Test for mice, experimental animals spent more time in the dark box and exhibited a decrease of the Rearing, presenting an anxious behavior; after the MPD medication, there were no more differences between experimental and control groups. Indiscriminate use of amphetamines has increased in recent years and this use, when not monitored, can cause serious adverse effects4. In this sense, ultradiluted medication can collaborate with the remission of possible undesirable effects. Conclusion: Initially, the MPD 30 CH changed the behavior shown by animals born from mothers that took methylphenidate during lactation and presented an anxious behavior as an unexpected effect. The mice that took the MPD 30 CH did not present the anxious behavior. Other experiments should be conducted to confirm the results of this study.

Placental Immune Tolerance and Organ Transplantation: Underlying Interconnections and Clinical Implications

The immune system recognizes and attacks non-self antigens, making up the cornerstone of immunity activity against infection. However, during organ transplantation, the immune system also attacks transplanted organs and leads to immune rejection and transplantation failure. Interestingly, although the embryo and placenta are semi-allografts, like transplanted organs, they can induce maternal tolerance and be free of a vigorous immune response. Also, embryo or placenta-related antibodies might adversely affect subsequent organ transplantation despite the immune tolerance during pregnancy. Therefore, the balance between the immune tolerance in maternal-fetal interface and normal infection defense provides a possible desensitization and tolerance strategy to improve transplantation outcomes. A few studies on mechanisms and clinical applications have been performed to explore the relationship between maternal-fetal immune tolerance and organ transplantation. However, up to now, the mechanisms underlying maternal-fetal immune tolerance remain vague. In this review, we provide an overview on the current understanding of immune tolerance mechanisms underlying the maternal-fetal interface, summarize the interconnection between immune tolerance and organ transplantation, and describe the adverse effect of pregnancy alloimmunization on organ transplantation.

Effect of maternal tolerance on behavioral problems in children with enuresis

Objective: To determine the effect of maternal tolerance on behavioral problems in children with enuresis. Method: A cross sectional descriptive study was conducted from January 2018 to November 2018 at three outpatient hospital settings in Pakistan. The sample comprised of 80 mothers (aged 23-50 years) having children with enuresis, who were recruited from one public (tertiary care) and two private (secondary care) outpatient hospital settings in Punjab. Participants were recruited after a formal diagnosis of enuresis made by the consultant pediatrician or psychiatrist. The Tolerance Scale and The Children Behavioural Questionnaire were used to assess maternal tolerance and behavioural problems in children, respectively. A demographics questionnaire with demographic details regarding the mother and the child, was also designed for the study. Results: The mean age of mothers (N=80) and their children was 34.53 ±4.89 years and 8.16 ± 2.36, respectively. Results of correlation analysis revealed that maternal intolerance was positively and significantly correlated with rule-breaking (r=.25, p=.02) and aggressive behaviors (r=.31, p=.01) in children with enuresis. In addition, linear regression analysis was carried out to observe if maternal tolerance significantly contributed to behavioural problems in children with enuresis. Maternal intolerance emerged as significant and positive predictor of rule-breaking behaviors (?=.25, p=.02), aggressive behaviors (?=.31, p=.00) and attention problems (?=.29, p=.01) in the affected children. Conclusion: The study demonstrates that maternal intolerance and hostile attitudes towards children with enuresis leads to secondary behavioural and emotional difficulties. Key Words: Enuresis, Maternal tolerance, Child health care, Continuous...

Tryptophan 2,3-Dioxygenase Expression Identified in Murine Decidual Stromal Cells Is Not Essential for Feto-Maternal Tolerance

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step of tryptophan catabolism along the kynurenine pathway, which has important immuno suppressive properties, particularly in tumor cells and dendritic cells. The prominent expression of IDO1 in the placenta also suggested a role in preventing immune rejection of fetal tissues, and pharmacological inhibition of IDO1 induced abortion of allogeneic fetuses in mice. However, this was later challenged by the lack of rejection of allogeneic fetuses in IDO1-KO mice, suggesting that other mechanisms may compensate for IDO1 deficiency. Here we investigated whether TDO could contribute to feto-maternal tolerance and compensate for IDO1 deficiency in IDO1-KO mice. Expression of TDO mRNA was previously detected in placental tissues. We developed a new chimeric rabbit anti-TDO antibody to confirm TDO expression at the protein level and identify the positive cell type by immunohistochemistry in murine placenta. We observed massive TDO expression in decidual stromal cells, starting at day E3.5, peaking at day E6.5 then declining rapidly while remaining detectable until gestation end. IDO1 was also induced in decidual stromal cells, but only at a later stage of gestation when TDO expression declined. To determine whether TDO contributed to feto-maternal tolerance, we mated TDO-KO and double IDO1-TDO-KO females with allogeneic males. However, we did not observe reduced fertility. These results suggest that, despite its expression in decidual stromal cells, TDO is not a dominant mechanism of feto-maternal tolerance able to compensate for the absence of IDO1. Redundant additional mechanisms of immunosuppression likely take over in these KO mice. The massive expression of TDO during decidualization might suggest a role of TDO in angiogenesis or vessel tonicity, as previously described for IDO1.

Allogeneic Embryos Disregulate Leukemia Inhibitory Factor (LIF) and Its Receptor in the Porcine Endometrium During Implantation

Despite its advantages for pig breeding, embryo transfer (ET) has a major handicap: high embryo mortality during the pre- and implantation period, probably caused by divergent phenomena of tolerance between the immunologically unrelated (i.e., allogeneic) embryos and the recipient sow. Thus, to reach a similar maternal tolerance as in conventional breeding by artificial insemination (AI) would be the key to ET-success. For this reason, we studied the expression of the leukemia inhibitory factor (LIF) cytokine and its receptor in the pig endometrium during the implantation period (days 18 and 24) in sows subjected to ET (AL group) vs. post-cervical-AI controls (Hemi-AL group). Quantification of expression was performed at both mRNA (rt-qPCR) and protein (WB) levels. The expression of endometrial LIF on day 24 was considerably lower in ET than in AI pregnancies. Correlations between endometrial mRNA levels of LIF and LIF-R showed that, contrary to early AI-pregnancies, ET-pregnancies lack an inverse relation between cytokine and receptor levels. In conclusion, ET-pregnancies lack sufficient endometrial levels of LIF to develop adequate immunotolerance mechanisms to prevent the rejection of allogeneic ET-embryos.

Gene expression of FOXP3, indoleamine 2,3-dioxygenase (IDO), IL10 and CSF1 in the uterus of cows that received an intrauterine infusion of maternal and paternal antigens

Sensitization with conceptus antigens has been shown to be useful for improving reproductive performance facilitating maternal acceptance of an allogeneic embryo through the induction of cytokines and immunoregulatory cells in the uterine microenvironment. As FOXP3, IDO, IL10 and CSF1 in the uterus are important on the recognition and development of embryos during early pregnancy, this study aimed to determine whether simultaneous or isolated administration of paternal (semen) and maternal (PBMCs) antigens in the uterus of cow, on the day of estrus, influence the gene expression of these cytokines. Forty crossbred cows were divided into four treatments: T0: Control; T1: Semen; T2: PBMCs (peripheral blood mononuclear cells) from another cow and T3: PBMCs+Semen. Antigens were administered into the uterine body on the estrus day (D0). Uterine biopsies designed for molecular analysis of gene expression were collected in vivo seven (D7) and fourteen (D14) days after immunostimulation. Transcripts from FOXP3, IDO, IL-10 and CSF-1 were detected in all RNA samples extracted from uterine biopsies. The semiquantitative analysis showed that none of the treatments caused significant increase in the expression of these genes. Furthermore, on D14 all treatments led to a decline in the number of CSF-1 transcripts; moreover, treatment with PBMCs+Semen also led to a drop in the abundance of IL-10 transcripts. Such results suggest that isolated or simultaneous administration of both antigens would not increase maternal tolerance to embryo alloantigens, nor would it create favorable conditions to its growth and pre-implantation development, at least regarding the effects mediated by these genes on D7 and D14 of the estrous cycle.

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

Preterm birth (PTB) complicates 5–18% of pregnancies globally and is a leading cause of maternal and fetal morbidity and mortality. Most PTB is spontaneous and idiopathic, with largely undefined causes. To increase understanding of PTB, much research in recent years has focused on using animal models to recapitulate the pathophysiology of PTB. Dysfunctions of maternal immune adaptations have been implicated in a range of pregnancy pathologies, including PTB. A wealth of evidence arising from mouse models as well as human studies is now available to support that PTB results from a breakdown in fetal-maternal tolerance, along with excessive, premature inflammation. In this review, we examine the current knowledge of the bidirectional communication between fetal and maternal systems and its role in the immunopathogenesis of PTB. These recent insights significantly advance our understanding of the pathogenesis of PTB, which is essential to ultimately designing more effective strategies for early prediction and subsequent prevention of PTB.

Role of galectin-glycan circuits in reproduction: from healthy pregnancy to preterm birth (PTB)

Growing evidence suggests that galectins, an evolutionarily conserved family of glycan-binding proteins, fulfill key roles in pregnancy including blastocyst implantation, maternal-fetal immune tolerance, placental development, and maternal vascular expansion, thereby establishing a healthy environment for the growing fetus. In this review, we comprehensively present the function of galectins in shaping cellular circuits that characterize a healthy pregnancy. We describe the current understanding of galectins in term and preterm labor and discuss how the galectin-glycan circuits contribute to key immunological pathways sustaining maternal tolerance and preventing microbial infections. A deeper understanding of the glycoimmune pathways regulating early events in preterm birth could offer the broader translational potential for the treatment of this devastating syndrome.