Cesarean delivery after successful external cephalic version of breech presentation at term: a comparative study

OBJECTIVE: The purpose of this study was to evaluate the rate and indications of cesarean delivery after a successful external cephalic version. STUDY DESIGN: A case-control study was performed from patients who were delivered in a tertiary care center between 1987 and 2000. Each patient who underwent a successful external cephalic version (study group) was compared with the next woman with the same parity, who was delivered at term (control group). Nulliparous and multiparous women were analyzed separately. Chi-squared, Mann-Whitney, and Student t tests were used for statistical analysis. Multivariate logistic regression analysis was performed where appropriate. RESULTS: A total of 602 patients were included in this study. The rates of cesarean delivery in nulliparous women (29.8% vs 15.9%; P<.001) and in multiparous women (15.9% vs 4.7%; P<.001) were significantly higher when compared with the control group. Patients with successful external cephalic version were more likely to have a cesarean delivery for dystocia (nulliparous, 22.5% vs 11.9%; P=.01; multiparous, 10.9% vs 1.3%; P<.01). After an adjustment for confounding variables, a successful external cephalic version was associated with an increased rate of cesarean delivery at term (nulliparous: odds ratio, 2.04; 95% CI, 1.13-3.68; multiparous: odds ratio, 4.30; 95% CI, 1.76-10.54). CONCLUSION: The rate of cesarean delivery for dystocia is increased after a successful trial of external cephalic version in both nulliparous and multiparous women.     

The relationship between amniotic fluid index and successful external cephalic version: a 14-year experience

OBJECTIVE: This study was undertaken to assess the association between amniotic fluid index (AFI), success of external cephalic version (ECV), and obstetric outcome in patients undergoing ECV. STUDY DESIGN: A prospective observational study was performed that included all patients who had a trial of ECV from 1987 to 2000 in our center. Rates of success, fetal heart decelerations during trial at ECV, and cesarean deliveries were calculated. Groups were divided by an AFI performed immediately before ECV: AFI less than 10 cm, 10 to 15 cm, and more than 15 cm. RESULTS: In our group of 1361 patients undergoing ECV, the rate of success was related to the AFI in both parous women (49.1%, 63.5% and 72.1% [P<.001] for each AFI group, respectively) and nulliparous women (36.5%, 43.6%, and 57.3% [P<.001]). The rate of cesarean section delivery was related to AFI in nulliparous but not multiparous patients (P<.001). The rate of prolonged fetal heart rate decelerations was not significantly related to the AFI. CONCLUSION: The rate of successful ECV and cesarean section deliveries is related to the amniotic fluid volume. This information may be used to consent patient before a trial of ECV.     

Improved brain uptake and pharmacological activity profile of morphine-6-glucuronide using a peptide vector-mediated strategy

Morphine-6-glucuronide (M6G), an active metabolite of morphine, has been shown to have significantly attenuated brain penetration relative to that of morphine. Recently, we have demonstrated that conjugation of various drugs to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated morphine-6-glucuronide to a peptide vector SynB3 to enhance its brain uptake and its analgesic potency after systemic administration. We show by in situ brain perfusion that vectorization of M6G (Syn1001) markedly enhances the brain uptake of M6G. This enhancement results in a significant improvement in the pharmacological activity of M6G in several models of nociception. Syn1001 was about 4 times more potent than free M6G (ED(50) of 1.87 versus 8.74 micromol/kg). Syn1001 showed also a prolonged duration of action compared with free M6G (300 and 120 min, respectively). Furthermore, the conjugation of M6G results in a lowered respiratory depression, as measured in a rat model. Taken together, these data strongly support the utility of peptide-mediated strategies for improving the efficacy of drugs such as M6G for the treatment of pain.     

Protein kinase C phosphorylates the inositol 1,4,5-trisphosphate receptor type 2 and decreases the mobilization of Ca2+in pancreatoma AR4-2J cells

In non-excitable cells, the inositol 1,4,5-trisphosphate receptor channel, which plays a major (IP(3)R) is an intracellular Ca(2+) role in Ca(2+) signalling. Three isoforms of IP(3)R have been identified (IP(3)R-1, IP(3)R-2 and IP(3)R-3) and most cell types express different proportions of each isoform. The differences between the pharmacological and functional properties of the various isoforms of IP(3)R are poorly understood. AR4-2J cells, which express almost exclusively (~86%) the IP(3)R-2, represent an interesting model to study this particular isoform. Here, we investigated a regulatory mechanism by which protein kinase C (PKC) influences IP(3)R-2-mediated Ca(2+) release. Using an immunoprecipitation approach, we confirmed that AR4-2J cells express almost exclusively the IP(3)R-2 isoform. Using an in vitro phosphorylation assay, we showed that the immunopurified IP(3)R-2 was efficiently phosphorylated by exogenous PKC. In intact AR4-2J cells metabolically labelled with (32)Pi, we showed that phorbol-12-myristate-13-acetate (PMA) and Ca(2+) mobilizing agonists cause the phosphorylation of IP(3)R-2. In saponin-permeabilized AR4-2J cells, IP(3)-induced Ca(2+) release was reduced after a pre-treatment with PMA or with exogenous PKC. PMA also reduced the Ca(2+) response of intact AR4-2J cells stimulated with carbachol and epidermal growth factor, two agonists that use different receptor types to activate phospholipase C. These results demonstrate that PKC decreases the Ca(2+)mobilizing activity of IP(3)R-2 and thus exerts a negative feedback on the agonists-induced Ca(2+) response of AR4-2J cells.     

HCV Spread Kinetics Reveal Varying Contributions of Transmission Modes to Infection Dynamics

The hepatitis C virus (HCV) is capable of spreading within a host by two different transmission modes: cell-free and cell-to-cell. However, the contribution of each of these transmission mechanisms to HCV spread is unknown. To dissect the contribution of these different transmission modes to HCV spread, we measured HCV lifecycle kinetics and used an in vitro spread assay to monitor HCV spread kinetics after a low multiplicity of infection in the absence and presence of a neutralizing antibody that blocks cell-free spread. By analyzing these data with a spatially explicit mathematical model that describes viral spread on a single-cell level, we quantified the contribution of cell-free, and cell-to-cell spread to the overall infection dynamics and show that both transmission modes act synergistically to enhance the spread of infection. Thus, the simultaneous occurrence of both transmission modes represents an advantage for HCV that may contribute to viral persistence. Notably, the relative contribution of each viral transmission mode appeared to vary dependent on different experimental conditions and suggests that viral spread is optimized according to the environment. Together, our analyses provide insight into the spread dynamics of HCV and reveal how different transmission modes impact each other.     

„Sind opioidfreie Anästhesie (OFA) und volatile Anästhetika wirklich die einzigen Wege? Ein kritischer Kommentar“

Die Anaesthesiologie -     

Experimental Investigation of Temperature and Contact Pressure Influence on HFI Welded Joint Properties

This paper presents an experimental electro-thermo-mechanical simulation of high-frequency induction (HFI) welding to investigate the effect of temperature and contact normal stress on the weld seam quality. Therefore welding experiments at different temperatures and contact pressures are performed using flat specimens of 34MnB5 steel sheet. In order to characterize the weld seam strength of the welded specimens, tensile and bending tests are performed. To obtain a relative weld seam strength, the bending specimens were additionally hardened prior to testing. With the hardened specimens, it can be shown that the weld seam strength increases with increasing temperature and contact normal stress until a kind of plateau is formed where the weld seam strength remains almost constant. In addition to mechanical testing, the influence of the investigated process parameters on the weld seam microstructure is studied metallographically using light optical microscopy, scanning electron microscopy, EBSD and hardness measurements. It is shown that the weld seam strength is related to the amount of oxides in the bonding line.     

Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing

High-grade B-cell lymphoma accompanied with double/triple-hit MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. In order to better understand the mutational and molecular landscape of HGBL-DH/TH we here performed whole-exome sequencing and deep panel next-generation sequencing of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features considering all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2-rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal center-derived B-cell lymphomas, this calls into question the current World Health Organization classification system, especially regarding the status of MYC/BCL6-rearranged HGBL.     

MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency

A cytotoxic T lymphocyte (CTL) clone was derived from a tumor-infiltrating lymphocyte (TIL) population infused to a melanoma patient who remained relapse free for 10 yr after this adoptive transfer. This clone recognized all melanoma cell lines tested and, to a lower extent, melanocytes, in the context of human histocompatibility leukocyte antigen A2 (HLA-A2), but it did not recognize other tumor cell types. The gene coding for the antigen recognized by this clone was identified by the screening of a melanoma complementary DNA expression library. This antigen is overexpressed in melanomas, compared with other cancer cell lines and healthy tissues, and was thus called melanoma-overexpressed antigen (meloe). Remarkably, the structure of meloe was unusual, with multiple short open reading frames (ORFs). The peptide recognized by the CTL clone was encoded by one of these ORFs, called MELOE-1. Using a specific HLA-A2/peptide tetramer, we showed a correlation between the infusion of TILs containing MELOE-1–specific T cells and relapse prevention in HLA-A2 patients. Indeed, 5 out of 9 patients who did not relapse were infused with TILs that contained MELOE-1–specific T cells, whereas 0 out of the 21 patients who relapsed was infused with such TIL-containing lymphocytes. Overall, our results suggest that this new antigen is involved in immunosurveillance and, thus, represents an attractive target for immunotherapy protocols of melanoma.