Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Intrahepatic cholestasis of pregnancy: an evaluation of obstetric management in German maternity units.

PURPOSE: Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse fetal and neonatal outcome. Evidence for improvement by obstetric management is sparse. Common international guidelines recommend induction of labor before term, however, they differ in recommendations of monitoring the disease and time point of active management. So far, an official guideline for treatment and management of ICP in Germany does not exist. This study aims to compile common practice and policy in obstetric management of ICP in German maternity units. The objective is to gather obstetricians' opinion on management of ICP, and to estimate the need for standardization of current practice in Germany on the background of existing evidence. METHODS: A questionnaire focusing on indications for interventions was developed including fourteen multiple-choice questions comprising the areas of diagnostic criteria, laboratory testing, fetal monitoring, treatment, and delivery timing. The survey was sent to 699 maternity clinics and was distributed to participants of the annual congress hosted by the German society of perinatal medicine (DGPM). Collected data were summarized and evaluated in relation to available evidence and existing guidelines. Descriptive statistics and Fisher's exact test were used. RESULTS: 334 completed questionnaires returned corresponding to a response rate of 48.1%. Coinciding with existing international guidelines, 48.8% of the participants acknowledge bile acid concentrations above 10 µmol/L to be indicative of ICP. 85.0% of obstetricians recommend antenatal testing with cardiotocography, exceeding common standards of maternity policy guidelines; 50.3% execute active management in ICP-affected pregnancies as they generally recommend a delivery between 37 + 0 and 38 + 6 weeks of gestation. Although recent studies evinced a risk of stillbirth in ICP-affected pregnancies not until a bile acid concentration of > 100 µmol/L, 22.2% of the respondents recommend delivery before 37 + 0 weeks of gestation due to raised bile acids of 40-99 µmol/L. CONCLUSIONS: Opinions on the management of ICP in German maternity units differ widely and partly deviate by large from international standards. Reasons for this may be the lack of a national guideline and the low awareness due to the rarity of the disease on the one hand and the very slow dynamics in evidence generation and thus the uncertainty about the actual risks and optimal management on the other. The present data highlight the need for further research and clinical guidelines to standardize and optimize treatment based on the best available evidence.

Antibody Response and Maternofetal Antibody Transfer in SARS-CoV-2-Positive Pregnant Women: A Multicenter Observational Study.

Introduction Awareness of SARS-CoV-2 infection in pregnant women and the potential risk for infection of their neonates is increasing. The aim of this study was to examine the immune status of affected women and evaluate the dynamics of placental antibody transfer. Materials and Methods The study included 176 women with SARS-CoV-2 infection during pregnancy who delivered between April 2020 and December 2021 at eight obstetric maternity sites. Demographic data, maternal and neonatal characteristics were summarized. Antibody testing for IgA and IgG in maternal blood sera and umbilical cord samples was evaluated and IgG transfer ratios were calculated. Values were related to the time of infection during pregnancy and birth. Results The percentage of IgG positive women increased from 29.0% (95% CI 23.8 - 37.8) at presentation with a positive PCR test result to 75.7% (95% CI 71.6 - 79.8), the percentage of IgG positive umbilical cord blood samples increased from 17.1% (95% CI 13.0 - 21.3) to 76.4% (95% CI 72.2 - 80.7) at more than six weeks after infection. Regression lines differed significantly between maternal and fetal IgG responses (p < 0.0001). Newborns react with a latency of about one week; umbilical cord blood antibody concentrations are highly correlated with maternal concentration levels (ρ = 0.8042; p < 0.0001). IgG transplacental transfer ratios were dependent on infection-to-birth interval. Two of the umbilical cord blood samples tested positive for IgA. Conclusions These findings confirm vertical SARS-CoV-2 transmission is rare; however, antibodies are transferred to the fetus soon after infection during pregnancy. Since transplacental antibody transfer might have a protective value for neonatal immunization this information may be helpful when counseling affected women.

[Does Apolipoprotein B Level in Early Pregnancy Predict Excessive Gestational Weight Gain and Adverse Pregnancy Outcome?] / Exzessive Gewichtszunahme in der Schwangerschaft und die prognostische Bedeutung des Apolipoprotein B.

INTRODUCTION: Excessive maternal gestational weight gain (GWG) is a risk factor for maternal and fetal complications. The lipid profile changes physiologically during pregnancy. Weight gain can affect lipid metabolism. The hypothesis of the study was that apoB levels early in pregnancy are associated with excessive GWG and predictive for adverse outcomes. METHODS: Out of 547 patients there were 95 women with inadequate GWG, 171 with adequate GWG, and 281 with excessive GWG. Out of 581 patients there were 14 patients with pregnancy-induced hypertonus/pre-eclampsia, 67 with small-for-gestational-age (SGA) infants, and 7 with fetal growth restriction (FGR). ApoB levels were measured by ELISA. RESULTS: There was no significant difference in apoB levels between the different GWG groups. We found significantly higher levels of apoB in overweight and obese patients compared to those with normal BMI. Smoking was correlated with higher apoB levels. There were no differences either between women with PIH/PE and normotensive women or between SGA/IUGR and pregnancies without. Women with pre-existing hypertension showed significantly higher apoB levels than the control group. CONCLUSIONS: ApoB cannot be used as a marker for identifying the risk of excessive GWG or adverse pregnancy outcomes early in pregnancy. However, it may be involved in the pathophysiology of adverse pregnancy outcomes in high-risk patients.

Estimating fetal cholesterol synthesis rates by cord blood analysis in intrauterine growth restriction and normally grown fetuses.

BACKGROUND: Cholesterol is an essential component in human development. In fetuses affected by intrauterine growth restriction (IUGR), fetal blood cholesterol levels are low. Whether this is the result of a reduced materno-fetal cholesterol transport, or due to low fetal de novo synthesis rates, remains a matter of debate. By analyzing cholesterol interbolites and plant sterols we aimed at deeper insights into transplacental cholesterol transport and fetal cholesterol handling in IUGR with potential targets for future therapy. We hypothesized that placental insufficiency results in a diminished cholesterol supply to the fetus. METHODS: Venous umbilical cord sera were sampled post-partum from fetuses delivered between 24 weeks of gestation and at full term. IUGR fetuses were matched to 49 adequate-for-age delivered preterm and term neonates (CTRL) according to gestational age at delivery. Cholesterol was measured by gas chromatography-flame ionization detection using 5a-cholestane as internal standard. Cholesterol precursors and synthesis markers, such as lanosterol, lathosterol, and desmosterol, the absorption markers, 5α-cholestanol and plant sterols, such as campesterol and sitosterol, as well as enzymatically oxidized cholesterol metabolites (oxysterols), such as 24S- or 27-hydroxycholesterol, were analyzed by gas chromatography-mass spectrometry, using epicoprostanol as internal standard for the non-cholesterol sterols and deuterium labeled oxysterols for 24S- and 27-hydroxycholesterol. RESULTS: Mean cholesterol levels were 25% lower in IUGR compared with CTRL (p < 0.0001). Lanosterol and lathosterol to cholesterol ratios were similar in IUGR and CTRL. In relation to cholesterol mean, desmosterol, 24S-hydroxycholesterol, and 27-hydroxycholesterol levels were higher by 30.0, 39.1 and 60.7%, respectively, in IUGR compared to CTRL (p < 0.0001). Equally, 5α-cholestanol, campesterol, and ß-sitosterol to cholesterol ratios were higher in IUGR than in CTRL (17.2%, p < 0.004; 33.5%, p < 0.002; 29.3%, p < 0.021). CONCLUSIONS: Cholesterol deficiency in IUGR is the result of diminished fetal de novo synthesis rates rather than diminished maternal supply. However, increased oxysterol- and phytosterol to cholesterol ratios suggest a lower sterol elimination rate. This is likely caused by a restricted hepatobiliary function. Understanding the fetal cholesterol metabolism is important, not only for neonatal nutrition, but also for the development of strategies to reduce the known risk of future cardiovascular diseases in the IUGR fetus.

Measurement and evaluation of fetal fat layer in the prediction of fetal macrosomia in pregnancies complicated by gestational diabetes.

OBJECTIVES: To explore the predictive power of measuring the abdominal fetal fat layer (FFL) as a soft tissue marker at 31, 34, and 37 weeks' gestation to improve the detection of fetal macrosomia in pregnant women with GDM, in addition to the biometric values with close monitoring of maternal blood sugar level and BMI changes. METHODS: We conducted a prospective observational study at the Department of Obstetrics, University Hospitals, Campus Kiel, Germany, in collaboration with diabetic clinic staff. Participants underwent a third-trimester scan and extra FFL measurements were performed at 31, 34, and 37 weeks of gestation. The clinical outcomes of pregnancy and birth weight were collected from the obstetric record. All of the enrolled women had an early pregnancy ultrasound scan to confirm gestational age. RESULTS: The FFL at 34 and 37 weeks, with respective cutoff values of >0.48 cm and >0.59 cm, showed a very good sensitivity of 60% for both gestational points, and specificity of 89.3 and 90.6%, respectively. The probability of fetal macrosomia could be more than doubled if the FFL at 34 weeks was more than 0.48 cm. However, the probability of macrosomia dropped to 16% if the FFL was ≤0.48 cm. The median FFLs of macrosomic fetuses at 34 and 37 weeks were 0.50 (IQR 0.10) and 0.60 (IQR 0.25) cm, respectively. The mean age of the study population (n = 80) was 32.26 (SD = 5.06) years. In our study population, ten newborns were born with birth weight >4000 g. The body mass index (BMI) for the mothers of later-onset macrosomic newborns showed higher median values of 30 (IQR 8), 32 (IQR 5), and 33 (IQR 9) at 31, 34, and 37 weeks, respectively, in comparison to mothers of non-macrosomic newborn. However, the BMI did not show any statistically significant difference from those with normal-weight newborn and did not show any specific sensitivity for predicting macrosomia. CONCLUSION: Measuring the FFL at 34 and 37 weeks of gestation, in addition to the standard measurement, might be useful for predicting macrosomia and is worth further evaluation.

Physical Exercise During Pregnancy - How Active Are Pregnant Women in Germany and How Well Informed?

INTRODUCTION: There is sufficient evidence showing the positive effects of physical exercise on various aspects of pregnancy. This study evaluates knowledge and status of physical exercise among pregnant women. METHODS: The standardised paper-pencil questionnaire "Pregnancy Physical Activity Questionnaire" (PPAQ) as well as general demographic questions were used to assess the exercise behaviour of study participants. 83 questionnaires completed by women presenting to the Kiel University Hospital for antenatal assessment were included in the analysis. RESULTS: At the time of questionnaire completion 10 women were in the first trimester of pregnancy, 64 in the second, and 9 in the third. Just less than 90% of participants felt they had been informed "sufficiently" on the topic physical exercise during pregnancy, over 50% felt they were "well" or "very well" informed. Just less than half of participants received their information from a doctor (either their gynaecologist or general practitioner) and none of these felt "insufficiently" informed. Almost 80% of participants reported still doing no sport or less exercise than before falling pregnant. The maximum proportional energy expenditure for recreational activity - just under 20% - was in the third trimester. Women who felt they had been well counselled tended to have higher activity levels. CONCLUSION: Study participants demonstrated a clear decline in physical exercise during pregnancy despite clear evidence of the benefits of regular exercise for pregnant women, and despite participants feeling they were well informed. Detailed information on the recommendations for physical exertion in pregnancy should form an integral part of antenatal counselling.

Validation of psychomotor tasks by Simbionix LAP Mentor simulator and identifying the target group.

BACKGROUND: This study addresses target group reliability and task validity for training on a laparoscopic simulator. MATERIAL AND METHODS: Data were collected on 64 participants prospectively at the Department of OB/GYN, University Hospitals Schleswig-Holstein, Campus Kiel. The Simbionix LAP Mentor for laparoscopic simulation was used to test trainees. Each participant received a questionnaire to clarify his/her medical position, surgical experience, and previous virtual reality (VR) experience, including video gaming experience. Pre- and post-tests were performed. Performances were analyzed for task completion and total time. RESULTS: All participants revealed a significant improvement in the post-test compared with the pre-test (p < .005), independent of their previous level of experience. Regarding accomplishment of the assigned task, the experts revealed in the pre-test an advantage in tasks 1-4 and 6-8. The beginners revealed wide-ranging improvements in tasks 3, 5, 8, and 9 between the pre-test and the post-test compared with novices in laparoscopic surgery (residents), and a wide range of improvements relative to experts. VR experience and video gaming exposure revealed an advantage in the pre-test; however, participants without previous exposure were able to narrow the gap, revealing extensive improvements in the post-test. CONCLUSION: The trainer could be beneficial for medical students and surgical novices.

Integration and Validation of Hysteroscopy Simulation in the Surgical Training Curriculum.

OBJECTIVE: The primary objective of our study was to test the construct validity of the HystSim hysteroscopic simulator to determine whether simulation training can improve the acquisition of hysteroscopic skills regardless of the previous levels of experience of the participants. The secondary objective was to analyze the performance of a selected task, using specially designed scoring charts to help reduce the learning curve for both novices and experienced surgeons. DESIGN: The teaching of hysteroscopic intervention has received only scant attention, focusing mainly on the development of physical models and box simulators. This encouraged our working group to search for a suitable hysteroscopic simulator module and to test its validation. We decided to use the HystSim hysteroscopic simulator, which is one of the few such simulators that has already completed a validation process, with high ratings for both realism and training capacity. As a testing tool for our study, we selected the myoma resection task. We analyzed the results using the multimetric score system suggested by HystSim, allowing a more precise interpretation of the results. SETTING: Between June 2014 and May 2015, our group collected data on 57 participants of minimally invasive surgical training courses at the Kiel School of Gynecological Endoscopy, Department of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Campus Kiel. PARTICIPANTS: The novice group consisted of 42 medical students and residents with no prior experience in hysteroscopy, whereas the expert group consisted of 15 participants with more than 2 years of experience of advanced hysteroscopy operations. RESULTS: The overall results demonstrated that all participants attained significant improvements between their pretest and posttests, independent of their previous levels of experience (p < 0.002). Those in the expert group demonstrated statistically significant, superior scores in the pretest and posttests (p = 0.001, p = 0.006). Regarding visualization and ergonomics, the novices showed a better pretest value than the experts; however, the experts were able to improve significantly during the posttest. These precise findings demonstrated that the multimetric scoring system achieved several important objectives, including clinical relevance, critical relevance, and training motivation. CONCLUSION: All participants demonstrated improvements in their hysteroscopic skills, proving an adequate construct validation of the HystSim. Using the multimetric scoring system enabled a more accurate analysis of the performance of the participants independent of their levels of experience which could be an important key for streamlining the learning curve. Future studies testing the predictive validation of the simulator and frequency of the training intervals are necessary before the introduction of the simulator into the standard surgical training curriculum.

Fetal gender and gestational age differentially affect PCSK9 levels in intrauterine growth restriction.

BACKGROUND: Maternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) concentrations are compromised in intrauterine growth restriction (IUGR). Generally, LDL-C catabolism is under control of PCSK9 by binding to the LDL-receptor leading to its degradation. Hence, we hypothesized a role for PCSK9 in the modulation of lipid metabolism and placental transport in IUGR. METHODS: 172 women, 70 IUGR and 102 controls were included in the study. Maternal and fetal serum PCSK9 levels and lipid profiles including LDL-C were measured. Placental LDL-receptor and PCSK9 expressions were estimated by tissue microarray immunohistochemistry, and analyzed by two blinded observers using an immunoreactivity score. Non-parametric tests and multivariate regression analyses were used for statistical estimations. RESULTS: PCSK9 levels in the maternal and fetal compartment independently predicted LDL-C levels (maternal compartment: adjusted R 2 = 0.2526; coefficient b i = 0.0938, standard error s bi =0.0217, rpartial = 0.4420, t-value = 4.323, p < 0.0001; fetal compartment: adjusted R 2 = 0.2929; b i = 0.1156, s bi =0.020, rpartial = 0.5494, t-value = 5.81, p < 0.0001). We did not find significant differences in maternal PCSK9 concentrations between IUGR and controls. However, we found lower fetal serum PCSK9 concentrations in IUGR than in controls (IUGR median 137.1 ng/mL (95% CI 94.8-160.0) vs. controls 176.8 (154.6-202.5), p = 0.0005). When subgrouping according to early onset, late onset IUGR, and fetal gender differences remained consistent only for male neonates born before 34 weeks of gestation. In the placenta we found no correlation between PCSK9 and LDL-receptor expression patterns. However, the LDL-receptor was significantly upregulated in IUGR when compared to controls (p = 0.0063). CONCLUSIONS: Our results suggest that PCSK9 play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender. This underlines the need to identify subgroups of IUGR that may benefit from individualized and gender-specific pharmacotherapy in future studies.

The Role of Interleukin-18 in Serum and Follicular Fluid during In Vitro Fertilization and Intracytoplasmic Sperm Injection.

Cytokines are key modulators of the immune system and play an important role in the ovarian cycle. IL-18 levels in serum and follicular fluid were analyzed in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. The cohort study group consisted of 90 women, who were undergoing IVF or ICSI. The body mass index (BMI) was determined in all patients; IL-18 levels were measured in follicular fluid and serum. IL-18 levels in serum were significantly higher than those in follicular fluid. The median level in serum was 162.75 (80.21) pg/mL and that in follicular fluid, 138.24 (91.78) pg/mL. Women undergoing IVF treatment had lower IL-18 levels in serum (median, 151.19 (90.73) pg/mL) than those treated with ICSI (median, 163.57 (89.97) pg/mL). The correlation between IL-18 levels in serum and BMI was statistically significant, as well as the correlation between IL-18 levels in follicular fluid and ovarian stimulation response (p = 0.003). IL-18 was correlated with the response to ovarian stimulation and was the reason for successful pregnancy after IVF or ICSI treatment. Among other cytokines, IL-18 appears to be a promising prognostic marker of success in reproductive treatment and should be evaluated as such in further prospective studies.

Safety and economical innovations regarding surgical treatment of fibroids.

Uterine leiomyomas are the most frequent benign tumors of the female genital tract. Fibroids are associated with a variety of clinical problems, e.g. bleeding disorders, bulk-related symptoms or infertility. For women wishing to preserve their uterus, fibroids can be surgically removed by hysteroscopy, laparoscopy or laparotomy. The purpose of our review is to show that hysterectomy offers the only definitive solution. The indication for treatment has to be taken carefully after weighing up alternative treatment methods, such as expectant management, medical treatment or interventional radiologic methods, and after obtaining informed consent. The optimal method of treatment takes into account the patient's interests and wishes and the practical feasibility in the clinical setup. Surgical skills and experience play an important role as surgical procedures on the uterus are not without risk and can lead to severe complications. The decision to operate anticipates an improvement of the initial situation; therefore, the ideal surgical approach is of utmost importance.

Macrophage colony-stimulating factor (M-CSF) in first trimester maternal serum: correlation with pathologic pregnancy outcome.

PURPOSE: To determine correlations between macrophage colony-stimulating factor (MCSF) levels in maternal blood during first trimester screening with respect to normal and pathological pregnancies. METHODS: This was a prospective single centre study. First trimester screening was performed according to FMF London certificates. Nuchal translucency, PAPP-A and free ß-HCG were obtained as well as M-CSF serum levels in maternal blood. Fetal karyotyping was achieved by chorionic villi sampling. RESULTS: 125 patients were enrolled in this study. 21 pregnancies had confirmed aberrant karyotypes. Trisomy 21 cases showed significantly elevated M-CSF levels of 270 ± 91 pg/ml (p = 0.032), whereas cases of trisomy 13 (183 ± 68 pg/ml) and trisomy 18 (143 ± 40 pg/ml) had low M-CSF levels. Furthermore M-CSF levels tended to be low in preterm deliveries, placental insufficiency and nicotine consumption. In cases with gestational diabetes M-CSF tended to be elevated. Furthermore we found a positive correlation between high free ß-human chorionic gonadotropin (hcg) and MCSF values. There was no correlation between pregnancy associated plasma protein (PAPP-A) and M-CSF. CONCLUSIONS: M-CSF is a cytokine promoting placental growth and differentiation. M-CSF is known to be involved in the process of implantation in pregnancy. The role of M-CSF with respect to disturbed pregnancy outcomes such as placental insufficiency in normal or aberrant karyotypes, for example, is yet subject to further research.

Cut-Off Levels of Anti-Mullerian Hormone for The Prediction of Ovarian Response, In Vitro Fertilization Outcome and Ovarian Hyperstimulation Syndrome.

BACKGROUND: Evaluation of anti-mullerian hormone (AMH) cut-off levels in as- sisted reproductive technology (ART) as predictive factor for individualization of stimulation protocols and to avoid ovarian hyperstimulation syndrome (OHSS). MATERIALS AND METHODS: In a retrospective study, 177 infertile patients were as- sessed for AMH in serum and follicular fluid (FF) on the day of follicular puncture (FP), between 2012 and 2013 in Kiel, Germany. AMH levels and pregnancy rates were compared between low, moderate and high responders and cut-off levels of low and high responders. AMH cut-off levels in pathological cases were evaluated in analysis 1 (OHSS) and in analysis 2 [polycystic ovarian syndrome, (PCOS)] and compared in analysis 3 to normal endocrinological parameters. RESULTS: AMH levels in FF were higher than in serum (P<0.001). AMH levels in serum and FF increased from low through moderate to high responders (P<0.001). Pregnancy rates were 14.7, 23.3 and 44.9% (P=0.009), respectively. AMH cut-off level for poor responders was 0.61 ng/ml in serum with a pregnancy rate of 13.8 and 37.1% for below and above of this level, respectively. For FF, it was 1.43 ng/ml. AMH levels in analysis 1 and 2 were significantly higher than in analysis 3 (P=0.001). AMH cut-off level for OHSS was 1.5 ng/ml in serum with OHSS rates of 80.8 and 19.2 % for above and below of the level, respectively. For FF, it was 2.7 ng/ml. PCOS patients had an AMH cut-off level of 3.9 ng/ml in serum and 6.8 ng/ml in FF, resulting in a PCOS rate of 100% above this level. CONCLUSION: AMH levels can help to assess ovarian response potential and guide ovarian stimulation while avoiding OHSS.

Factors to consider in gynecological surgery.

Progress is evident in the whole concept of breast cancer treatment and in the assessment of the sentinel node in different cancers of the female in urogynecology, as well as in minimally invasive surgery. In this review we concentrate on the impact of endoscopic surgery. Minimally invasive surgery has evolved in a relatively short period of time to overtake the centuries old visionary and pioneering groundwork of outstanding colleagues in all surgical disciplines. This overview on the development of gynecological surgery highlights past achievements and describes present challenges of endoscopic surgery. It emphasizes future opportunities and possibilities to foster interdisciplinary collaboration and integrate emerging endoscopic, imaging and stereotactic surgical technologies to improve patient safety, enhance quality of care and advance surgical education.

Distended jugular lymphatic sacs in fetuses with increased nuchal translucency: correlation with first-trimester findings in aberrant karyotypes.

OBJECTIVE: We investigated the prognostic relevance of ultrasound visibility of distendend jugular lymphatic sacs (JLS) in fetuses with aberrant karyotypes in First-trimester-screening. Furthermore we tried to differentiate between increased nuchal translucency (NT) and cystic hygroma colli. METHODS: We performed a retrospective single center study in 1874 patients presenting for First-trimester-screening between 2009 and 2013. All fetuses with an abnormal risk calculation and NT > 2.5 mm (95th percentile) were reviewed for ultrasound visibility of JLS. A group of 30 fetuses with normal risk calculation served as control. Karyotyping was performed by chorionic-villi-sampling or amniocentesis, respectively. RESULTS: In a total of 2030 fetuses 70 (3.44%) with pathologic first-trimester-screening results showed either aberrant karyotypes or severe ultrasound pathologies. Main aberrant karyotypes were trisomy 21 (25), trisomy 18 (16), trisomy 13(six), Monosomy X (four), 47, XYY or 47, XXX (three) and Noonan' syndrome (two). Distended JLS were visible in 47% of all cases. Statistical anaylsis found a significant correlation between NT and JLS size for the fetuses with trisomies 21, 18 and 13 (r = 0.53, p < 0.002). Cystic hygroma colli was present in all Turner and Noonan syndromes. CONCLUSIONS: Distended JLS have a strong correlation with abnormal karyotypes and increased nuchal translucency. Karyotyping should be offered in these cases.

Intra-operative use of one-step nucleic acid amplification (OSNA) for detection of the tumor load of sentinel lymph nodes in breast cancer patients.

BACKGROUND: The purpose of this single-center study was to determine the practicability of the intra-operative use of one-step nucleic acid amplification (OSNA) as the only method for detection of SLN. The OSNA system has been well described and is supposed to be as accurate as conventional histology. METHODS: Three hundred and thirty SLNs from 143 breast cancer patients were analyzed in an intra-operative setting. The CK19-copy number was determined by OSNA and divided into 3 results ("-" no metastasis; "+" micrometastasis; "++" marcometastasis). If OSNA gave a positive result, an axillary lymph node dissection was carried out during the same session. The central 1-mm slice of each node was obtained for permanent histology. Additionally, the results were correlated to clinicopathological factors, and the time for the intra-operative use was evaluated. RESULTS: Thirty-nine of the 143 patients were OSNA positive, 22 with macrometastatic and 17 with micrometastatic spread. The mean time for the OSNA run with one SLN was 34.4 min. We could show a correlation between the tumor size and OSNA positivity as well as between the numbers of OSNA positive SLNs with the tumor load of associated non-SLNs. Furthermore, we found that a cutoff CK19 copy number of 7,900/µL indicates a positive non-SLN result with the highest sensitivity (91 %) and specificity (61 %). CONCLUSION: We found OSNA to be very helpful for the intra-operative determination of the tumor load of a SLN as a basis for decision-making concerning further surgical axillary intervention. OSNA allows precise differentiation of micro- from macrometastasis, and the CK19 copy number predicts the probability of tumor load in other axillary lymph nodes and might help to find adequate adjuvant treatment options. This objective method is well suitable for everyday use and may reduce the pathologic workload and the risk of secondary operative interventions with all associated costs and stress for the patients.

Aurora kinase inhibitor AZD1152 has an additional effect of platinum on a sequential application at the human ovarian cancer cell line SKOV3.

PURPOSE: The treatment of ovarian tumors is carried out with platinum medicine which can lead to incompatibilities or resistances. Thus, it is of great interest to check new medicine suitability for its application. AZD1152 is an Aurora kinase inhibitor predominantly works against Aurora kinase B involved in the chromosome segregation. Cells become polyploidy and reduce the proliferation by this impairment. To investigate whether AZD1152, may play a role in the treatment of ovarian carcinoma we serving it to the cisplatinum-resistant cell line SKOV3 alone and in combination with platinum. METHODS: We look at the proliferation, the ploidy, the phases of cell cycle and the apoptosis activity of the cells. RESULTS AND CONCLUSION: We could show that the combination of both medicines in the preclinical experiment produces a working advantage.