HIV-1 Infection of Long-Lived Hematopoietic Precursors In Vitro and In Vivo.

Latent reservoirs in human-immunodeficiency-virus-1 (HIV-1)-infected individuals represent a major obstacle in finding a cure for HIV-1. Hematopoietic stem and progenitor cells (HSPCs) have been described as potential HIV-1 targets, but their roles as HIV-1 reservoirs remain controversial. Here we provide additional evidence for the susceptibility of several distinct HSPC subpopulations to HIV-1 infection in vitro and in vivo. In vitro infection experiments of HSPCs were performed with different HIV-1 Env-pseudotyped lentiviral particles and with replication-competent HIV-1. Low-level infection/transduction of HSPCs, including hematopoietic stem cells (HSCs) and multipotent progenitors (MPP), was observed, preferentially via CXCR4, but also via CCR5-mediated entry. Multi-lineage colony formation in methylcellulose assays and repetitive replating of transduced cells provided functional proof of susceptibility of primitive HSPCs to HIV-1 infection. Further, the access to bone marrow samples from HIV-positive individuals facilitated the detection of HIV-1 gag cDNA copies in CD34+ cells from eight (out of eleven) individuals, with at least six of them infected with CCR5-tropic HIV-1 strains. In summary, our data confirm that primitive HSPC subpopulations are susceptible to CXCR4- and CCR5-mediated HIV-1 infection in vitro and in vivo, which qualifies these cells to contribute to the HIV-1 reservoir in patients.

Vaginal breech delivery of pregnancy before and after the estimated due date-A prospective cohort study.

INTRODUCTION: 3-4% of pregnant women present with a fetal breech position at term. National societies regard vaginal breech delivery as a safe option, but only for a specific and thoroughly counseled group of patients. To avoid adverse outcome, many practitioners recommend elective cesarean section once their patients go past the estimated due date. Since encompassing evidence is missing, the evaluation on this common clinical practice is needed. OBJECTIVE: This study compares the short-term maternal and fetal outcome in intended vaginally breech deliveries before the estimated due date (until 40 0/7 weeks of gestation) to the outcome of deliveries carried out past the estimated due date (later than 40 0/7 weeks of gestation). METHODS: This prospective cohort study includes 827 women who presented for an intended vaginal breech delivery of a singleton at our perinatal center between January 2010 and December 2016. RESULTS: 447 patients (54%) delivered before or at their estimated due date, 380 (46%) of pregnancies continued after the estimated due date. Comparing both groups, no significant difference in maternal and neonatal short-term mortality and morbidity was found. The rate of caesarian sections was increased in the group of patients, who delivered later than 40 1/7 weeks of gestation. Here, the likelihood for delivery maneuvers was also increased. CONCLUSION: This study provides evidence, that an elective cesarean section for breech presentations at term is not obligatory when the estimated due date has passed in singleton pregnancy.

Maternal and neonatal outcome after vaginal breech delivery of nulliparous versus multiparous women of singletons at term-A prospective evaluation of the Frankfurt breech at term cohort (FRABAT).

INTRODUCTION: The best way to deliver a term breech infant is still a much discussed topic among obstetricians. The question whether nulliparity should be considered an exclusion criterion for an intended vaginal breech delivery is not fully answered. OBJECTIVE: We compared maternal and neonatal outcome of intended vaginal breech deliveries of nulliparous versus multiparous women at term. STUDY DESIGN: We conducted a prospective case-control study between January 2004 and December 2016. 1046 women expecting singletons at term with favorable pelvic measurements were enrolled in the study. RESULTS: Neonatal morbidity and mortality was not significantly different in deliveries of nulliparous (n = 647) versus multiparous (n = 399) women. Nulliparous women had a significantly higher rate of a cesarean section during labor than multiparous women. Maternal birth-injury rates and the use of epidural anesthesia were significantly higher comparing vaginal births of nulliparous (n = 384) versus multiparous (n = 331) women. CONCLUSION: Nulliparity seems not be an exclusion criterion for intended vaginal breech birth at term. It is still important to inform the women of an increased risk of a cesarean section during labor. A clinical management built on this evidence might reduce negative implications for future pregnancies.

The influence of the fetal leg position on the outcome in vaginally intended deliveries out of breech presentation at term - A FRABAT prospective cohort study.

INTRODUCTION: Vaginal delivery out of a breech presentation in pregnancies at term are being re-implemented into clinical practice. Still, recommendations regarding exclusion criteria leading to caesarean sections are based on expert opinions, not on evidence-based guidelines. The difference in perinatal outcome and course of delivery in births with babies in frank breech position and babies in incomplete or complete breech presentation never has been investigated in a large patient cohort. OBJECTIVE: To compare perinatal outcome of vaginally intended breech deliveries between births out of frank breech position and incomplete/complete breech presentation. DESIGN: Prospective cohort study. SAMPLE: 884 women at term with a singleton in frank breech presentation (FB) and 284 women with incomplete or complete breech presentation (CB) intending vaginal birth between January 2004 and December 2018. METHODS: Maternal and fetal outcome was compared between groups using Pearson's Chi Square test. Birth duration parameters were analysed using logistic regression. RESULTS: There were no differences in cesarean section rates (FB: 25.1%, CB 22.2%, p = 0.317). Short-term fetal morbidity did not differ between groups (FB: 2.5%, CB: 2.8%, p = 0.761). In vaginal deliveries the necessity to perform manual assistance was significantly more frequent in deliveries of infants in CB (FB: 39.9%, CB: 51.6%, p = 0.0013). Cord loops (FB: 10.1%, CB: 18.0%, p = 0.0004) and cesarean sections necessary because of cord prolapses (FB: 1.4%, CB 8.1%, p = 0.005) were significantly more often in deliveries with babies in CB. CONCLUSION: This study provides evidence, that perinatal morbidity is not associated with the fetal leg posture in vaginally intended breech deliveries. The higher risk for the need of manual assistance during vaginal birth in deliveries of babies out of complete or incomplete breech presentation suggests that obstetrical departments re-implementing the vaginal breech in their repertoire might start with births of babies out of frank breech presentation.

Maternal and neonatal outcome after vaginal breech delivery at term of children weighing more or less than 3.8 kg: A FRABAT prospective cohort study.

INTRODUCTION: The clinical management of breech presentations at term is still a controversially discussed issue among clinicians. Clear predictive criteria for planned vaginal breech deliveries are desperately needed to prevent adverse fetal and maternal outcomes and to reduce elective cesarean section rates. The green-top guideline considers an estimated birth weight of 3.8 kg or more an indication to plan a cesarean section despite the lack of respective evidence. OBJECTIVE: To compare maternal and neonatal outcome of vaginal intended breech deliveries of births with children with a birth weight of 2.5 kg- 3.79 kg and children with a birth weight of 3.8 kg and more. DESIGN: Prospective cohort study. SAMPLE: All vaginal intended deliveries out of a breech position of newborns weighing between 2.5 kg and 4.5 kg at the Obstetrics department at Goethe University Hospital Frankfurt from January 2004 until December 2016. METHODS: Neonatal and maternal outcome of a light weight group (LWG) (< 3.8 kg) was compared to and a high weight group (HWG) (≥ 3.8 kg) using Pearson's Chi Square test and Fishers exact test. A logistic regression analysis was performed to detect an association between cesarean section rates, fetal outcome and the birth weight. RESULTS: No difference in neonatal morbidity was detected between the HWG (1.8%, n = 166) and the LWG (2.6%, n = 888). Cesarean section rate was significantly higher in the HWG with 45.2% in comparison to 28.8% in the LWG with an odds ratio of 1.57 (95% CI 1.29-1.91, p<0.0001). In vaginal deliveries, a high birth weight was not associated with an increased risk of maternal birth injuries (LWG in vaginal deliveries: 74.3%, HWG in vaginal deliveries: 73.6%; p = 0.887; OR = 1.9 (95% CI 0.9-1.1)). CONCLUSION: A fetal weight above 3.79 kg does not predict increased maternal or infant morbidity after delivery from breech presentation at term. Neither the literature nor our analyses document evidence for threshold of estimated birth weight that is associated with maternal and/or infant morbidity. However, patients should be informed about an increased likelihood of cesarean sections during labor when attempting vaginal birth from breech position at term in order to reach an informed shared decision concerning the birth strategy. Further investigations in multi center settings are needed to advance international guidelines on vaginal breech deliveries in the context of estimated birth weight and its impact on perinatal outcome.

Primary Cilia Are Dysfunctional in Obese Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.

Involvement of the oncogene B-cell lymphoma 6 in the fusion and differentiation process of trophoblastic cells of the placenta.

The oncogene B-cell lymphoma 6 (BCL6) is associated with lymphomagenesis. Intriguingly, its expression is increased in preeclamptic placentas. Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity. Preeclamptic placentas are characterized by various defects like deregulated differentiation and impaired fusion of trophoblasts. Its pathogenesis is however not totally understood. We show here that BCL6 is present throughout the cell fusion process in the fusogenic trophoblastic cell line BeWo. Suppression of BCL6 promotes trophoblast fusion, indicated by enhanced levels of fusion-related ß-hCG, syncytin 1 and syncytin 2. Increased mRNA levels of these genes could also be observed in primary term cytotrophoblasts depleted of BCL6. Conversely, stable overexpression of BCL6 reduces the fusion capacity of BeWo cells. These data suggest that an accurately regulated expression of BCL6 is important for proper differentiation and successful syncytialization of trophoblasts. While deregulated BCL6 is linked to lymphomagenesis by blocking lymphocyte terminal differentiation, increased BCL6 in the placenta contributes to the development of preeclampsia by impairing trophoblast differentiation and fusion.