T. W. Goecke

Breakdown of the Endothelial Barrier Function in Tumor Cell Transmigration

The ability of tumor cells to metastasize is associated with a poor prognosis for cancer. During the process of metastasis, tumor cells circulating in the blood or lymph vessels can adhere to, and potentially transmigrate through, the endothelium and invade the connective tissue. We studied the effectiveness of the endothelium as a barrier against the invasion of 51 tumor cell lines into a three-dimensional collagen matrix. Only nine tumor cell lines showed attenuated invasion in the presence of an endothelial cell monolayer, whereas 17 cell lines became invasive or showed a significantly increased invasion. Endothelial cells cocultured with invasive tumor cells increased chemokine gene expression of IL-8 and Gro-β. Expression of the IL-8 and Gro-β receptor, CXCR2, was upregulated in invasive tumor cells. Addition of IL-8 or Gro-β increased tumor cell invasiveness by more than twofold. Tumor cell variants selected for high CXCR2 expression were fourfold more invasive in the presence of an endothelial cell layer, whereas CXCR2 siRNA knock-down cells were fivefold less invasive. We demonstrate that Gro-β and IL-8 secreted by endothelial cells, together with CXCR2 receptor expression on invasive tumor cells, contribute to the breakdown of the endothelial barrier by enhancing tumor cell force generation and cytoskeletal remodeling dynamics.

Weight estimation by three‐dimensional ultrasound imaging in the small fetus

To improve birth weight estimation in fetuses weighing ⩽ 1600 g at birth by deriving a new formula including measurements obtained using three‐dimensional (3D) sonography.

Differences in gene expression dependent on sampling site in placental tissue of fetuses with intrauterine growth restriction

OBJECTIVE The human placenta as part of the feto-placental unit may influence fetal endocrine systems and may therefore represent a very important link between intrauterine growth restriction (IUGR) and metabolic disorders in later life. We aimed to analyze the effect of sample origin on gene expression of placental factors potentially involved in fetal programming in IUGR versus appropriate for gestational age growth (AGA) to standardize sample collection procedure for a multicenter approach. DESIGN Placental gene expression of insulin-like growth factor-binding protein (IGFBP)-1, prolactin, corticotropin releasing hormone (CRH) and leptin was measured and compared between proximal, intermediate and peripheral region of the placenta in 22 IUGR (proven by anomalous placental Doppler velocimetry) and 19 AGA neonates. RESULTS Whereas no difference in gene expression was seen in the proximal portion, in the intermediate placental region mRNA expression of IGFBP-1 (p = 0.01), prolactin (p = 0.04), CRH (p = 0.01) and leptin (p = 0.04) was increased in IUGR samples compared to controls. At the placental periphery, gene expression of these placental transcripts showed a higher expression level in IUGR placentas without statistical significance, except for leptin (p = 0.03). CONCLUSION Placental sampling site seems to be relevant for detecting differences in gene expression between IUGR and AGA neonates.

Genetic variants in the tryptophan hydroxylase 2 gene (TPH2) and depression during and after pregnancy

BACKGROUND A number of studies indicate that altered serotonergic transmission may be a risk factor for depression in the peripartum period. The aim of this study was to investigate whether genetic polymorphisms in the TPH2 gene, the gene product of which is the rate-limiting enzyme in the biosynthesis of serotonin in the central nervous system, are associated with depressive symptoms in pregnancy and the postpartum period. METHODS In a cohort of 361 Caucasians, the severity of depression was assessed prospectively during pregnancy (third trimester) and the postpartum period (2-3 days and 6-8 months) using the Edinburgh Postnatal Depression Scale (EPDS). Tagging single nucleotide polymorphisms (SNPs) in TPH2 and SNPs that are known to be of functional relevance were genotyped. For each haplotype block or SNP, a multifactorial linear mixed model was performed to analyse the EPDS values over time. RESULTS The haplotype block in the promoter region of TPH2 showed significant associations with depression values during pregnancy and 6-8 months afterwards. Additionally, a haplotype block in intron 8 had an influence on depression values during pregnancy, but not after birth. There was a significant interaction between time and haplotypes and the severity of depression. The effect of TPH2 haplotypes on EPDS values was strongest during pregnancy and 6 months after birth, with a low depression rating in the first few days after delivery for all women. CONCLUSIONS In this cohort, TPH2 haplotypes known to be of functional relevance were found to be associated with different EPDS values during and after pregnancy. These haplotypes were associated with depressive symptoms both before and after delivery and were thus not specific for postpartum-onset depression. This underlines the relevance of these functional polymorphisms for depression in general and the importance of longitudinal assessments in research on postpartum depression.

Two naturally occurring variants of the serotonin receptor gene HTR3C are associated with nausea in pregnancy

Objective. To assess the association between pregnancy‐associated symptoms and common single nucleotide polymorphisms (SNPs) in genes known to be involved in the pathogenesis of nausea and vomiting. Design. In a standardized, questionnaire‐based interview, women selected from a control cohort for association studies were asked retrospectively about nausea and vomiting during their first pregnancy. Population. A total of 593 women who had completed at least one pregnancy and for whom germline DNA was available were selected. Methods. Eight SNPs in the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D, HTR3E, and NK1R (TACR1) were tested using polymerase chain reaction. The occurrence of nausea and vomiting was correlated with the patients’ genotyping results and medical history parameters. Results. Both young age at first pregnancy and positive smoking status were significantly associated with vomiting and nausea during pregnancy. After adjustment for these two parameters, the two SNPs rs6806362 (odds ratio (OR) 1.38 per allele; 95% confidence interval (CI) 1.06–1.79; p = 0.017) and rs6807670 (OR 1.37; 95% CI 1.05–1.79 per allele; p = 0.023) were marginally associated with pregnancy‐related nausea. None of the other polymorphisms showed any association. Conclusion. Polymorphisms in the subunit gene HTR3C of the serotonin receptor may be involved in the pathogenesis of pregnancy‐associated nausea.

Increased uterine arterial pressure and contractility of perfused swine uterus after treatment with serum from pre-eclamptic women and endothelin-1

The present study was designed to examine the effects of ET-1 (endothelin-1) and serum from PE (pre-eclamptic), HP (healthy pregnant) and HNP (healthy non-pregnant) women on uterine arterial perfusion pressure and uterine contractility. Swine uteri (n = 25) were perfused for a period of up to 11 h, with the aim being to preserve a viable organ. Various concentrations of ET-1 as well as serum from PE, HP and HNP women (n = 10 per group) were administered to the perfused swine uteri and IUP (intrauterine pressure) and IAP (intra-arterial pressure) were recorded. ET-1 produced dose-dependent increases in IUP and IAP. The ET-1 concentration in serum was higher in serum from PE women than in HP and HNP women (P > 0.05). Administration of all serum samples had a contractile effect on the swine uterus, with the greatest effect being seen in HNP women (12.8 +/- 5.3 mmHg), followed by PE (9.06 +/- 4.2 mmHg) and HP (6.1 +/- 4.1 mmHg) women. Statistically significant differences were observed between HNP and PE women (P = 0.048), and PE and HP women (P = 0.021). Increases in IAP following administration of serum from PE women (48.8 +/- 20.0 mmHg) were significantly higher (P = 0.024) compared with the effect of serum from HP women (28.4 +/- 13.7 mmHg). In conclusion, the findings show that serum from PE women has significant vasoconstrictive and oxytocic effects compared with serum from HP women. In pre-eclampsia, the balance between vasorelaxing and vasoactive substances is disturbed.

First retransplantation of cryopreserved ovarian tissue following cancer therapy in Germany.

INTRODUCTION New anticancer treatments have increased survival rates for cancer patients but often at the cost of sterility. One way of preserving fertility in these patients is the use of cryopreservation of ovarian tissue with subsequent retransplantation following a period of recurrence-free survival. We report the follow-up of the first case of retransplantation of ovarian tissue in Germany. METHODS Immediately following the diagnosis of anal cancer, ovarian tissue was removed laparoscopically, and cryopreserved. The patient was then treated with combined radiochemotherapy, which resulted in iatrogenic premature ovarian failure, and was associated with inhibin B serum levels lower than 10 ng/L. After the 2.5 year period of cancer remission, the cryopreserved ovarian tissue was retransplanted orthotopically. RESULTS Five months later estradiol serum levels had risen from lower than 20 pg/mL to 436 pg/mL. Three ovarian follicles were detected ultrasonographically in the pelvic side wall. Finally the patient reported her first menstruation after the intervention. The endocrine activity of the transplanted cryopreserved tissue has demonstrated viability, and the ability to develop. DISCUSSION Cycle monitoring and timed intercourse should now help to achieve conception. These first results from Germany for retransplantation of cryopreserved ovarian tissue clearly show its potential for preserving fertility.

Treatment of heterotopic cervical pregnancies.

OBJECTIVE To describe a rare case of a heterotopic pregnancy with a gestational sac in the cervix and one in the uterine cavity, managed successfully with subsequent delivery of a healthy newborn. DESIGN Case report and review of the literature. SETTING Tertiary university hospital. PATIENT(S) A woman with heterotopic twin gestation after stimulation treatment at 9 weeks gestation. Transvaginal ultrasound scan revealed two gestational sacs containing two viable fetuses: one sac inside the uterine cavity and the other sac in the uterine cervix. INTERVENTION(S) Selective termination of the cervical pregnancy by curettage under sonographic guidance in combination with cervical cerclage. MAIN OUTCOME MEASURE(S) Intrauterine pregnancy preservation; maternal morbidity and mortality. RESULT(S) The termination of the cervical pregnancy was performed successfully without intraprocedural or postprocedural complications with preservation of the patients fertility. The intrauterine pregnancy progressed uneventfully through 39½ weeks with delivery of a healthy newborn. CONCLUSION(S) Combined intrauterine and cervical pregnancy is a remote but possible event, particularly after assisted reproductive technology procedures with a high rate of maternal morbidity. Other factors such as concomitant intrauterine pregnancy and the patients infertility history generally would be secondary concerns. In this case, we were able to terminate the cervical pregnancy selectively, while preserving the intrauterine one, allowing this couple to have a healthy newborn.

Prenatal and adult androgen activities in alcohol dependence

Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their childrens prenatal androgen load.

How Good is Fetal Weight Estimation Using Volumetric Methods

PURPOSE Birth weight is an important predictive parameter for neonatal morbidity and mortality, and accurate estimation of fetal weight is therefore a valuable tool for determining the further obstetric management. Many sonographic weight formulas have been introduced. Most of these widely accepted formulas were derived from non-linear regression analysis. Only few formulas have been constructed using other methods, such as the physically based volumetric method based on routine two-dimensional biometric parameters in the fetus. The rationale for calculating fetal weight from volumetric measurements was that weight should to be directly proportional to fetal volume. In a recent review by Dudley, this method was considered to have some advantages in comparison with conventional regression formulas. However, to the best of our knowledge, none of the published volumetric formulas has ever been evaluated in a large population of fetuses. The aim of this study was to compare the volumetry-based formulas with widely accepted weight equations derived from regression analysis. We evaluated weight equations over the whole weight range and in specific weight groups in order to find out whether some equations were preferable in the groups tested. MATERIALS AND METHODS 3975 pregnancies were included in order to evaluate four conventional formulas and four formulas based on volumetric models. The inclusion criteria were a singleton pregnancy, ultrasound examination with complete biometric parameters within 7 days before delivery, and an absence of structural or chromosomal malformations. The equations were compared over the whole weight range and in specific weight groups. RESULTS Over the whole weight range, no single formula was able to offer a substantial advantage. In the small fetus, the Hadlock formula was preferable due to its low level of systematic error. For mid-sized fetuses, the Schild formula should be considered. In macrosomic fetuses, all formulas tended to underestimate the actual birth weight. Here, the best accuracy was achieved using the Merz formula. CONCLUSION Neither a volumetric formula nor a conventional formula proved to be superior over the whole weight range. Within specific weight groups, some formulas showed improved accuracy. However, new approaches such as three-dimensional ultrasonography need to be pursued further in order to achieve better results in fetal weight estimation.