Markus Hoopmann

Acetylcholine Receptor Pathway Mutations Explain Various Fetal Akinesia Deformation Sequence Disorders

Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.

Cisplatin, doxorubicin and paclitaxel induce mdr1 gene transcription in ovarian cancer cell lines

The clinical observation of the multidrug resistance (MDR) phenotype is often associated with overexpression of the mdrl gene, in particular with respect to ovarian cancer. However, until now the mdrl-inducing potential of commonly used antineoplastics has been only incompletely explored. We performed short-term cultures of six ovarian cancer cell lines (MZOV4, EF027, SKOV3, OAW42, OTN14, MZOV20) exposed to either blank medium or cisplatin, doxorubicin or paclitaxel at concentrations related to the clinically achievable plasma peak concentration. A highly specific quantitative real-time RT-PCR was used to detect the Mdr1 transcripts. Mdrl mRNA contents were calibrated in relation to coamplified GAPDH mRNA. Mdrl mRNA was detectable in each cell line. In 13 out of 18 assays (72%) the specific anticancer drug being tested induced mdr1 transcription. No decrease in mdr1 mRNA concentration was observed. Our data suggest that mdr1 induction by antineoplastics is one of the reasons for failure of ovarian cancer therapy but may vary individually.

Idiopathic polyhydramnios and postnatal abnormalities.

Objective: To investigate the proportion and type of fetal anomalies that are associated with polyhydramnios and to examine whether in cases with idiopathic polyhydramnios during the course of pregnancy and fetal anomalies only diagnosed after birth, antenatal characteristics differ. Methods: This was a retrospective study involving all pregnancies with polyhydramnios defined by a deepest pool of amniotic fluid ≥8 cm and a detailed ultrasound examination, a 75 g glucose tolerance test and a TORCH serology. Results: Between 2004 and 2010, 272 pregnancies fulfilled the inclusion criteria. In 89 (32.7%) and 65 (23.9%) cases, there was a fetal anomaly or diabetes. In 118 (43.4%) pregnancies, polyhydramnios was classified as idiopathic. In 11 (9.3%) of the 118 fetuses, an anomaly was found after birth, mainly gastrointestinal atresia. In these cases, median deepest pool of amniotic fluid was 9.6 cm, and median estimated fetal weight was at the 69th centile, whereas in cases without anomalies diagnosed after birth, median deepest pool was 9.0 cm and median estimated fetal weight at the 90th centile (Mann-Whitney U test: deepest pool p = 0.116, and estimated fetal weight centile p = 0.377). There was also no difference in the maternal and gestational age distribution of these cases (Mann-Whitney U test: maternal age p = 0.293, and gestational age p = 0.499). Conclusion: In about 40% of pregnancies, polyhydramnios remains unexplained during the course of pregnancy. In 10% of these cases, an anomaly will only be found after birth. In this group, antenatal characteristics such as amniotic fluid volume, estimated fetal weight or gestational and maternal age at the time of diagnosis do not help to detect these anomalies before birth.

Specific weight formula for fetuses with abdominal wall defects

To develop and to evaluate a specific sonographic weight formula for fetuses with abdominal wall defects.

The V109G Polymorphism of the p27 Gene CDKN1B Indicates a Worse Outcome in Node-Negative Breast Cancer Patients

Although p27 plays a central role in cell cycle regulation, its role in breast cancer prognosis is controversial. Furthermore, the p27 gene CDKN1B carries a polymorphism with unknown functional relevance. This study was designed to evaluate p27 expression and p27 genotyping with respect to early breast cancer prognosis. 279 patients with infiltrating metastasis-free breast cancer were included in this study. p27 expression was determined in tumor tissue specimens from 261 patients by immunohistochemistry. From 108 patients, the CDKN1B genotype was examined by PCR and subsequent direct sequencing. 55.2% of the tumors were considered p27 positive. p27 expression did not correlate with any of the established parameters except for nodal involvement but significantly correlated to prolonged disease-free survival. In 35% of the tumors analyzed, the CDKN1B gene showed a polymorphism at codon 109 (V109G). The V109G polymorphism correlated with greater nodal involvement. In the node-negative subgroup, V109G correlated significantly with a shortened disease-free survival. In conclusion, the determination of the CDKN1B genotype might be a powerful tool for the prognosis of patients with early breast cancer.

Time to progression is dependent on the expression of the tumour suppressor PTEN in ovarian cancer patients

Background Quantitative analyses of PTEN expression of ovarian cancer tissues were performed in this study. PTEN expression was investigated in terms of each patients progression‐free interval to indicate the role of PTEN in the generation of platinum refractory tumours.

Case report: Heterotopic triplet pregnancy with bilateral tubal and intrauterine pregnancy after IVF

Heterotopic pregnancy in a spontaneous cycle is rare, but the incidence increases with the introduction of assisted reproductive technologies. This report describes a case of combined bilateral tubal and intrauterine pregnancy after IVF and embryo transfer. The diagnostic and therapeutic problems will be discussed both in terms of the case report and the literature. Heterotopic pregnancies after IVF and resulting problems are further reasons to encourage the transfer of only one embryo. This could be difficult to achieve without simultaneously decreasing pregnancy rates, as embryo selection is not permitted in Germany.

Relaxin expression correlates significantly with serum fibrinogen variation in response to antidiabetic treatment in women with type 2 diabetes mellitus

Aim. Diabetes is associated with aberrant coagulation. Relaxin, an insulin-like peptide hormone, is a candidate to be involved in the underlying molecular mechanisms. Therefore, the present study investigated the correlation of relaxin expression with fibrinogen levels in diabetes patients undergoing oral antidiabetic treatment. Method. In total, 192 type 2 diabetes patients were enrolled into the study. The patients were randomized to receive either pioglitazone or glimepiride for 26 weeks. Blood was drawn at baseline and at the end of the study to measure the concentrations of relaxin and fibrinogen with an enzyme-linked immunosorbent assay and a turbimetric method, respectively. In addition, platelets were counted at both time points. Results. Total datasets were available from 161 patients (age 62.5 ± 8.1 years, mean ± standard deviation; 58 women, 103 men). The median initial parameter concentrations were: relaxin, 27.4 pg/ml (range 0.4 – 380 pg/ml); fibrinogen, 3.0 g/l (range 1.1 – 7.9 g/l); platelets, 217 000/μl (range 51 000 – 547 000/μl). The data were analyzed according to the increase or decrease of each parameter after therapy compared with baseline. There was a significant correlation of relaxin variation with fibrinogen variation, seen particularly in the female subgroup (p < 0.05). The correlation was independent of the antidiabetic medication. Conclusion. The data suggest that there is a correlation between fibrinogen levels and relaxin expression. Relaxin may exert its cardioprotective properties after pathologic fibrinogen increase. This regulation may be affected by diabetes. As a consequence, cardiovascular risk may increase in women with aberrant relaxin functionality.

The Diagnosis and Treatment of Ectopic Pregnancy

BACKGROUND Extrauterine pregnancy is a complication of the first trimester of pregnancy that arises in 1.3-2.4% of all pregnancies. METHODS This review is based on articles and guidelines retrieved by a selective PubMed search. RESULTS The presentation of extrauterine pregnancy is highly variable, ranging from an asymptomatic state, to pelvic pain that is worse on one side, to tubal rupture with hemorrhagic shock. 75% of tubal pre gnancies can be detected by transvaginal ultrasonography. In patients with a vital extrauterine pregnancy, the human chorionic gonadotropin concentration generally doubles within 48 hours. Laparoscopy is the gold standard of treatment. Two randomized, controlled trials comparing organ-preserving treatment with ablative surgery revealed no significant difference in pregnancy rates after the intervention, but precise details of the surgical procedures were not provided, and long-term fertility data are lacking. Metho - trexate therapy should be used only for strict indications. CONCLUSION Further randomized, controlled trials with longer follow-up will be needed to answer currently open questions about the potential for individualized surgical treatment and the proper role of pharmacotherapy.

Do Specific Weight Formulas for Fetuses ≤ 1500 g Really Improve Weight Estimation?

PURPOSE In addition to gestational age, fetal weight is an important predictive parameter for neonatal morbidity and mortality in very small fetuses. In order to improve weight estimation, specific weight formulas for fetuses under 1500 g have been introduced by several authors. The aim of the present study was therefore to compare specific weight equations for fetuses under 1500 g with widely used methods that were designed for the whole fetal weight range. MATERIALS AND METHODS 459 pregnancies were included in order to evaluate six widely used formulas and four formulas specifically designed for very small fetuses. The inclusion criteria were a singleton pregnancy, birth weight equal to or less than 1500 g, ultrasound examination with complete biometric parameters during the 7 days prior to delivery, and an absence of structural or chromosomal malformations. RESULTS All formulas, except the Hadlock equations, demonstrated a significant systematic error. Regarding the random error, it was similar for most of the methods. The Scott formula showed the narrowest limits of agreement. At a discrepancy level of 5 % and 10 % between estimated fetal weight and actual birth weight, one of the Hadlock formulas included the most cases. CONCLUSION Weight formulas, specifically designed for very small fetuses, do not improve sonographic weight estimation substantially. Among these formulas, the Scott equation was the most accurate one. However compared to the widely used Hadlock formulas, it was not favorable.