Sonographic examination at the beginning of the second stage of labor predicts birth outcome in vaginally intended breech deliveries: a blinded prospective study.

PURPOSE: In order to spread competence in vaginal breech deliveries, it is necessary to develop new and easily applicable tools for birth progression and safety evaluation. Ultrasound is a useful and ubiquitously available tool with already documented value for birth progression observation. In deliveries out of breech presentation, an established ultrasound examination is missing. We determined the descent of the fetal buttocks in relation to the maternal pelvic inlet using intrapartum ultrasound. We evaluated these results in comparison to the clinical vaginal examination with the aim to establish an easily applicable method for birth outcome prediction. Therefore, we analyzed the predictive value of our examinations on birth outcome parameters, such as cesarean section rate, as well as fetal and maternal outcome parameters. METHODS: We performed a prospective blinded study on 106 mothers with vaginally intended breech delivery. At beginning of stage two in labor, the descent of the fetal buttocks into the mother's pelvic inlet was detected with transabdominal ultrasound and vaginal examination by different observers. PRIMARY OUTCOME VARIABLE: Cesarean section rate. Secondary outcome variables: rate of manual assistance in vaginal deliveries, birth duration, 5' APGAR score, umbilical arterial pH, maternal blood loss, and perineal injury. For non-parametric values, Wilcoxon's χ2 test was performed. In order to analyze the predictive value of our examination, lack-of-fit analysis was conducted. Reliability evaluation of the sonographic examination was done with a matched-pair analysis. RESULTS: Women with positive intrapartum ultrasound breech engagement sign (+ IPUBES) had a significantly lower rate of cesarean section in comparison with those with negative IPUBES (5/67; 7.5% vs. 18/39; 46.2%; p < 0.0001). The area under the ROC curve for the prediction of CS for negative IPUBES was 0.765 with a sensitivity of 78.3% and a specificity of 74.7%. Sonographic examination showed an excellent reliability in a matched-pair analysis comparing vaginal and sonographic examinations with a mean difference of 0.012 (SD ± 0.027, 95% CI - 0.014 to 0.065). Mean birth duration was significantly longer in deliveries with negative IPUBES (533 min vs. 440 min; p = 0.0011). Fetal and maternal outcome parameters were not significantly different between deliveries with positive and negative IPUBES. CONCLUSIONS: Sonographic evaluation of the fetal descent in relation to the mother's pelvic inlet screens reliably for emergency cesarean section. This newly presented method for birth progression observation might be a powerful tool for distribution of expertise in vaginal breech delivery and is able to give reference for clinical vaginal examination by obstetricians in training. TRAIL REGISTRY: Clinical trial. Date of registration: 13.03.2019; Date of initial participant enrollment: 20.03.2019; DRKS00016885; https://www.drks.de ; German clinical trials register.

Differences in Biometric Fetal Weight Estimation Accuracy and Doppler Examination Results in Uncomplicated Term Singleton Pregnancies between Vertex and Breech Presentation.

Doppler examination of the umbilical artery and the fetal middle cerebral artery is evaluated predominantly in pregnancies with fetuses in cephalic presentation and never has been elucidated in breech presentation. Evidence on the accuracy of fetal weight estimation in dependence of the fetal presentation is controversial. Nevertheless, clinical decisions including recommendations for a cesarean section or labor induction based on these examinations are applied to pregnancies with fetuses in breech presentation. The objective of this study was to investigate the influence of the fetal presentation on fetal weight estimation accuracy, umbilical artery and middle cerebral artery resistance indices (RI) in a prospective case control study. Ultrasound examinations in 305 uncomplicated term pregnancies (153 vertex presentations, 152 breech) were investigated. Non-parametric variables were compared using Pearson's chi2 test and Wilcoxon chi2 test, depending on variable scaling. Fetal weight estimation accuracy was not significantly different between vertex presentation group (VP) (6.97%) and breech presentation group (BP) (7.96%, p = 0.099). Fetal head circumference measurements were significantly larger in BP (350 mm vs. 341 mm in VB, p > 0.0001) while abdominal circumferences were significantly smaller (VP: 338 mm, BP: 331 mm, p = 0.0039) and weight estimation was not significantly different. Umbilical artery RIs were not significantly different between VP (54.5) and BP (55.3, p = 0.354). Fetal middle cerebral artery RIs also showed no significant differences (VP: 71.2, BP: 70.7, p = 0.335). Our study shows that fetal Doppler (RI) and weight estimation ultrasound originally calibrated in cephalic pregnancies are applicable to pregnancies with fetuses in breech presentation.

Learning Breech Birth in an Upright Position Is Influenced by Preexisting Experience-A FRABAT Prospective Cohort Study.

BACKGROUND: Vaginal breech delivery is becoming an extinct art although national guidelines underline its safety and vaginal breech delivery in an upright position has been shown to be a safe birth mode option. In order to spread clinical knowledge and be able to implement vaginal breech delivery into obstetricians' daily practice, we need to gather knowledge from facilities who teach specialized obstetrical management. METHODS: We performed a prospective cohort study on 140 vaginal deliveries out of breech presentation solely-managed by seven newly-trained physicians and compared fetal outcome as well as rates of manual assistance in respect to preexisting experience. RESULTS: Fetal morbidity rate measured with a modified PREMODA score was not significantly different in three sub-cohorts sorted by preexisting expertise levels of managing obstetricians (experience groups EG, EG0: 2, 5%; EG1: 3, 7.5%; EG2: 1, 1.7%; p = 0.357). Manual assistance rate was significantly higher in EG1 (low experience level in breech delivery and only in dorsal position) compared to EG0 and EG2 (EG1 28, 70%; EG0: 14, 25%; EG2: 21, 35%; p = 0.0008). CONCLUSIONS: Our study shows that vaginal breech delivery with newly-trained obstetricians is a safe option whether or not they have advanced preexisting expertise in breech delivery. These data should encourage implementing vaginal breech delivery in clinical routine.

Obesity Epidemic-The Underestimated Risk of Endometrial Cancer.

Endometrial cancer (EC) is the most frequently observed malignant gynecologic disease in developed countries. There is a strong association between the established risk factor obesity and the incidence of EC. Furthermore, the rate of women with a body mass index (BMI) > 30 kg/m2 is increasing worldwide, correspondingly leading to a higher prevalence of EC. Understanding the adipose tissue as an endocrine organ, elementary pathophysiological pathways of tumorigenesis have been revealed. This includes the fundamental role of hyperglycemia, insulin resistance, and hyperestrogenemia, as well as interactions with a chronic proinflammatory microenvironment. Therapeutic options potentially include metformin or bariatric surgery. Moreover, changes in individual lifestyle such as weight reduction, physical activity, and an awareness of healthy nutrition are effective in preventing the disease.

Primary Cilia in Trophoblastic Cells: Potential Involvement in Preeclampsia.

The pathogenesis of preeclampsia, a pregnancy-related disease, is not completely understood. The primary cilium transduces a diverse array of signaling pathways important for vital cellular activities. Primary cilia were reported to facilitate trophoblastic cell invasion. We hypothesized their further functions in trophoblasts and were interested in related molecular mechanisms. We systematically examined the presence, length and percentage of the primary cilium, its mediated signal transduction, and its connection to trophoblast function. Various cellular and molecular methods were used including immunofluorescence staining, spheroid formation, gene analysis, invasion and tube formation assays with trophoblastic cell lines, primary trophoblasts, and placental tissues. We show that primary cilia are present in various trophoblastic cell lines derived from first trimester placentas. Cilia are also observable in primary trophoblasts, though in a small quantity. Importantly, primary cilia are shortened in trophoblastic cells derived from preeclamptic placentas. Mechanistically, interleukin-6, tumor necrosis factor-α or sera from patients with preeclampsia are able to reduce the length of primary cilia and impair the important sonic hedgehog signaling pathway. Functionally, trophoblastic cells with defective cilia display severe failures in their key functions, like migration, invasion and tube formation, also observed in trophoblastic cells depleted of the intraflagellar transport protein 88. This is accompanied by reduced gene expression of matrix metallopeptidases, vascular endothelial growth factor, and placental growth factor. This work highlights the significance of primary cilia in the functions of trophoblastic cells. Dysfunctional cilia may lead to compromised migration, invasion, and endothelial remodeling of trophoblastic cells, contributing to the development of preeclampsia.

Restoration of primary cilia in obese adipose-derived mesenchymal stem cells by inhibiting Aurora A or extracellular signal-regulated kinase.

BACKGROUND: Obesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs). ASCs are indispensable for tissue homeostasis/repair, immunomodulation, and cell renewal. It has been demonstrated that obese ASCs are defective in differentiation, motility, immunomodulation, and replication. We have recently reported that some of these defects are linked to impaired primary cilia, which are unable to properly convey and coordinate a variety of signaling pathways. We hypothesized that the rescue of the primary cilium in obese ASCs would restore their functional properties. METHODS: Obese ASCs derived from subcutaneous and visceral adipose tissues were treated with a specific inhibitor against Aurora A or with an inhibitor against extracellular signal-regulated kinase 1/2 (Erk1/2). Multiple molecular and cellular assays were performed to analyze the altered functionalities and their involved pathways. RESULTS: The treatment with low doses of these inhibitors extended the length of the primary cilium, restored the invasion and migration potential, and improved the differentiation capacity of obese ASCs. Associated with enhanced differentiation ability, the cells displayed an increased expression of self-renewal/stemness-related genes like SOX2, OCT4, and NANOG, mediated by reduced active glycogen synthase kinase 3 ß (GSK3ß). CONCLUSION: This work describes a novel phenomenon whereby the primary cilium of obese ASCs is rescuable by the low-dose inhibition of Aurora A or Erk1/2, restoring functional ASCs with increased stemness. These cells might be able to improve tissue homeostasis in obese patients and thereby ameliorate obesity-associated diseases. Additionally, these functionally restored obese ASCs could be useful for novel autologous mesenchymal stem cell-based therapies.

Pre-systemic elimination of tilidine: localization and consequences for the formation of the active metabolite nortilidine.

The therapeutic activity of tilidine, an opioid analgesic, is mainly related to its active metabolite nortilidine. Nortilidine formation mainly occurs during the high intestinal first-pass metabolism of tilidine by N-demethylation. Elimination of the active nortilidine to the inactive bisnortilidine is also mediated by N-demethylation and is supposed to take place in the liver, probably at a smaller rate. The aim of this study was the investigation of the pre-systemic elimination of tilidine using grapefruit juice (GFJ) as an intestinal CYP3A4 inhibitor and efavirenz (EFV) as a CYP3A4 activator. A randomized, open, placebo-controlled, cross-over study was conducted in 12 healthy volunteers using 100 mg tilidine solution p.o., regular strength GFJ 250 mL (3 times at 12-hr intervals) and EFV 400 mg (12 hr before tilidine administration). Tilidine, nortilidine and bisnortilidine in plasma and urine were quantified by a validated LC/MS/MS analysis. GFJ did not change any pharmacokinetic parameter of tilidine and its metabolites, which suggests that intestinal CYP3A4 does not contribute to the first-pass metabolism of tilidine. No effect of EFV on the pharmacokinetics of the active nortilidine was observed except a significant reduction of the terminal elimination half-life by 15%. Overall elimination (renal and metabolic clearances) was unaffected by every treatment. CYP3A4 does not seem to play a major role in tilidine first-pass and overall metabolism. Other unknown metabolites and their enzymes responsible for their formation have to be investigated as they account for the majority of renally excreted metabolites.

Concentration effect relationship of CYP3A inhibition by ritonavir in humans.

PURPOSE: To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity. METHODS: An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1-300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance. RESULTS: Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure-inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2-4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed. CONCLUSIONS: Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.

[Biologics - nomenclature and classification]. / Nomenklatur und Einteilung von Biologicals.

Biological medicines are a heterogeneous group of drugs that are produced by living organisms using genetic or biological technology. Unlike chemically derived small molecules biologics are structurally complex making characterization and manufacturing difficult. Moreover, biological medicines show a great variety concerning their clinical use. To appropriately consider these particularities, there are other standards and guidelines for approval of similar derivatives of biologics, the so-called biosimilars or follow-on biologics. In contrast to a generic medicinal product containing a chemically identical active ingredient, a biosimilar is only expected to be similar to the innovator drug. Nowadays, monoclonal antibodies, fragments of antibodies, and fusion proteins manufactured by recombinant procedures play an important role. They have been used in many specialties for diagnostic and therapeutic purposes and are subject to continuous further development and improvement. Their nomenclature is based on a classification by the WHO which allows drawing conclusions for class of substance, origin, and pharmacological target.

Breast cancer cell-derived cytokines, macrophages and cell adhesion: implications for metastasis.

BACKGROUND: Liver metastasis is associated with a proinflammatory microenvironment and up-regulation of cell adhesion molecules expressed by endothelial cells. The aim of this study was to characterize the interrelations between breast cancer cell-secreted cytokines, macrophages and E-selectin-mediated cancer cell adhesion and their role in metastasis of breast cancer. MATERIALS AND METHODS: Three metastatic breast cancer cell lines (1590, KM22, ZE) were studied. Cell culture supernatants were screened for cytokines and the potential for cytokines to increase tumor-necrosis factor-α (TNF-α) production by ANA-1-macrophages was analyzed. E-Selectin-mediated tumor cell adhesion of fluorescence labelled tumor cells was evaluated by measurement of fluorescence intensity with and without E-selectin-blocking strategies (monoclonal antibodies, cimetidine). RESULTS: Tumor-specific cytokine secretion patterns were revealed. TNF-α secretion from cultured macrophages increased after incubation with tumor supernatants. Tumor cell adhesion was significantly inhibited by cimetidine and monoclonal antibodies against E-selectin (KM22 with cimetidine, p<0.05). CONCLUSION: Breast cancer cell-secreted cytokines stimulate macrophages to produce TNF-α, a known up-regulator of E-selectin expression, and therefore cell adherence to endothelium. Inhibition of this mechanism could be an attractive therapeutic option for the prevention of breast cnacer metastasis.