Publications by authors named "Constantin S von Kaisenberg"

34 Publications

The cumulative impact of parity on the body mass index (BMI) in a non-selected Lower Saxony population.

J Perinat Med 2020 Dec 1. Epub 2020 Dec 1.

Department of Obstetrics and Gynecology, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

Objectives: During the last decade obesity has been continuously rising in adults in industrial countries. The increased occurrence of perinatal complications caused by maternal obesity poses a major challenge for obstetricians during pregnancy and childbirth. This study aims to examine the association between parity, pregnancy, birth risks, and body mass index (BMI) of women from Lower Saxony, Germany.

Methods: This retrospective cohort study examined pseudonymized data of a non-selected singleton cohort from Lower Saxony's statewide quality assurance initiative. Mothers were categorized according to BMI as normal weight (18.5 to <25 kg/m2) or obese (≥30 kg/m2).

Results: Most of the mothers in this study population were either in their first (33.9%) or second pregnancy (43.4%). The mean age of women giving birth for the first time was 28.3 years. Maternal age increased with increasing parity. The proportion of pregnant women with a BMI over 30 was 11% in primiparous women, 14.3% in second para, 17.3% in third para and 24.1% in fourth para or more women. Increasing parity was positively correlated with the incidence of classical diseases related to obesity, namely diabetes mellitus, gestational diabetes, hypertension, pregnancy-related hypertension and urinary protein excretion. An increased risk of primary or secondary cesarean section was observed in the obese women, particularly during the first deliveries.

Conclusions: There is a positive and significant correlation between parity and increased maternal BMI. The highest weight gain happens during the first pregnancy. The rate of operative deliveries and complications during delivery is increased in obese pregnant women.
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http://dx.doi.org/10.1515/jpm-2020-0261DOI Listing
December 2020

Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro.

J Clin Med 2021 Jan 6;10(2). Epub 2021 Jan 6.

Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.

Endothelial dysfunction is a primary feature of several cardiovascular diseases. Endothelial colony-forming cells (ECFCs) represent a highly proliferative subtype of endothelial progenitor cells (EPCs), which are involved in neovascularization and vascular repair. Statins are known to improve the outcome of cardiovascular diseases via pleiotropic effects. We hypothesized that treatment with the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor pravastatin increases ECFCs' functional capacities and regulates the expression of proteins which modulate endothelial health in a favourable manner. Umbilical cord blood derived ECFCs were incubated with different concentrations of pravastatin with or without mevalonate, a key intermediate in cholesterol synthesis. Functional capacities such as migration, proliferation and tube formation were addressed in corresponding in vitro assays. mRNA and protein levels or phosphorylation of protein kinase B (AKT), endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1), vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and endoglin (Eng) were analyzed by real time PCR or immunoblot, respectively. Proliferation, migration and tube formation of ECFCs were enhanced after pravastatin treatment, and AKT- and eNOS-phosphorylation were augmented. Further, expression levels of HO-1, VEGF-A and PlGF were increased, whereas expression levels of sFlt-1 and Eng were decreased. Pravastatin induced effects were reversible by the addition of mevalonate. Pravastatin induces beneficial effects on ECFC function, angiogenic signaling and protein expression. These effects may contribute to understand the pleiotropic function of statins as well as to provide a promising option to improve ECFCs' condition in cell therapy in order to ameliorate endothelial dysfunction.
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http://dx.doi.org/10.3390/jcm10020183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825508PMC
January 2021

Low Ethanol Concentrations Promote Endothelial Progenitor Cell Capacity and Reparative Function.

Cardiovasc Ther 2020 22;2020:4018478. Epub 2020 Sep 22.

Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.

Background: Endothelial progenitor cells (EPCs) are recruited to injured endothelium and contribute to its regeneration. There is evidence that moderate ethanol consumption prevents the development and progression of atherosclerosis in a variety of and models and increases the mobilization of progenitor cells. Furthermore, there are studies that identified ethanol at low concentration as a therapeutic tool to mobilize progenitor cells in peripheral blood. At the same time, the cell number of EPCs represents a close link to cardiovascular system constitution and function and contributes to cardiovascular risk. The aim of this study was to evaluate the effect of low dose ethanol on typical features of endothelial colony-forming cells (ECFCs), a proliferative subtype of EPCs.

Methods And Results: We tested whether ethanol impacts the functional abilities of ECFC (e.g., migration, tube formation, and proliferation) using assays, the intercommunication of ECFC by exploring cell surface molecules by flow cytometry, and the expression of (anti-)angiogenic molecules by ELISA. Low concentrations of ethanol concentration promoted migration, proliferation, and tubule formation of ECFC. The expression of the cell surface marker VE-cadherin, a protein which plays an important role in cell-cell interaction, was enhanced by ethanol, while (anti-)angiogenic molecule expression was not impacted.

Conclusion: Ethanol at moderate concentrations increases the angiogenic abilities of endothelial progenitor cells thus possibly contributing to vasoprotection.
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http://dx.doi.org/10.1155/2020/4018478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528128PMC
November 2020

Vitamin D improves endothelial barrier integrity and counteracts inflammatory effects on endothelial progenitor cells.

FASEB J 2019 08 14;33(8):9142-9153. Epub 2019 May 14.

Gynecology Research Unit, Hannover Medical School, Hannover, Germany.

Endothelial colony-forming cells (ECFCs), a proliferative subpopulation of endothelial progenitor cells, are involved in angiogenesis and endothelial repair. In this study, we investigated endothelial barrier characteristics of ECFCs, whether vitamin D supports cell-cell adhesion and barrier integrity, and how it affects ECFC mobilization and actin dynamics. Although ECFC barrier was disrupted under inflammatory conditions, this effect was rescued by vitamin D treatment, leading to higher stability of an ECFC monolayer. Furthermore, vitamin D enhanced ECFC mobilization toward directional migration. In addition, immunocytochemistry, quantitative real-time PCR, and immunoblotting analysis showed that vitamin D increased endothelial interconnections through vascular endothelial cadherin (VE-cadherin) junctions and by impacting cell dynamics through cofilin and VE-cadherin phosphorylation. Our results suggest that vitamin D treatment efficiently counteracts inflammation in an ECFC monolayer, resulting in higher ECFC barrier integrity. This study provides evidence of a new beneficial effect of vitamin D for ECFC homeostasis.-Schröder-Heurich, B., von Hardenberg, S., Brodowski, L., Kipke, B., Meyer, N., Borns, K., von Kaisenberg, C. S., Brinkmann, H., Claus, P., von Versen-Höynck, F. Vitamin D improves endothelial barrier integrity and counteracts inflammatory effects on endothelial progenitor cells.
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http://dx.doi.org/10.1096/fj.201802750RRDOI Listing
August 2019

Preeclampsia-Associated Alteration of DNA Methylation in Fetal Endothelial Progenitor Cells.

Front Cell Dev Biol 2019 19;7:32. Epub 2019 Mar 19.

Department of Obstetrics and Gynecology, Hannover Medical School, Hanover, Germany.

Objective: The pregnancy complication preeclampsia represents an independent risk factor for cardiovascular disease. Our previous research shows a diminished function of fetal endothelial colony-forming cells (ECFC), a proliferative subgroup of endothelial progenitor cells (EPC) in preeclampsia. The aim of this study was to further investigate whether DNA methylation of fetal EPC is affected in preeclampsia.

Methods: The genomic methylation pattern of fetal ECFC from uncomplicated and preeclamptic pregnancies was compared for 865918 CpG sites, and genes were classified into gene networks. Low and advanced cell culture passages were compared to explore whether expansion of fetal ECFC in cell culture leads to changes in global methylation status and if methylation characteristics in preeclampsia are maintained with increasing passage.

Results: A differential methylation pattern of fetal ECFC from preeclampsia compared to uncomplicated pregnancy was detected for a total of 1266 CpG sites in passage 3, and for 2362 sites in passage 5. Key features of primary networks implicated by methylation differences included cell metabolism, cell cycle and transcription and, more specifically, genes involved in cell-cell interaction and Wnt signaling. We identified an overlap between differentially regulated pathways in preeclampsia and cardiovascular system development and function. Cell culture passages 3 and 5 showed similar gene network profiles, and 1260 out of 1266 preeclampsia-associated methylation changes detected in passage 3 were confirmed in passage 5.

Conclusion: Methylation modification caused by preeclampsia is stable and detectable even in higher cell culture passages. An epigenetically modified endothelial precursor may influence both normal morphogenesis and postnatal vascular repair capacity. Further studies on epigenetic modifications in complicated pregnancies are needed to facilitate development of EPC based therapies for cardiovascular alterations.
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http://dx.doi.org/10.3389/fcell.2019.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436196PMC
March 2019

Associations between the Level of Trace Elements and Minerals and Folate in Maternal Serum and Amniotic Fluid and Congenital Abnormalities.

Nutrients 2019 Feb 3;11(2). Epub 2019 Feb 3.

Institute of Human Nutrition and Dietetics, Poznan University of Life Sciences, Poznan, Poland, ul. Wojska Polskiego 31, 60-624 Poznan, Poland.

Congenital birth defects may result in a critical condition affecting the baby, including severe fetal/neonatal handicap and mortality. Several studies have shown that genetic, nutritional, and environmental factors may have an impact on fetal development and neonatal health. The relevance of essential and toxic elements on fetal development has not yet been fully investigated, and the results of recent research indicate that these elements may be crucial in the assessment of the risk of malformations in neonates. We determined the association between essential and toxic elements and the level of folate in maternal serum (MS) and amniotic fluid (AF), along with neonatal abnormalities. A total of 258 pregnant Polish women in the age group of 17⁻42 years participated in this study. AF and MS were collected during vaginal delivery or during cesarean section. An inductively coupled plasma mass spectrometry technique was used to determine the levels of various elements in AF and MS. The results of this exploratory study indicate that the levels of essential and toxic elements are associated with fetal and newborn anatomical abnormalities and growth disorders.
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http://dx.doi.org/10.3390/nu11020328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413094PMC
February 2019

S100-alarmin-induced innate immune programming protects newborn infants from sepsis.

Nat Immunol 2017 06 1;18(6):622-632. Epub 2017 May 1.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.

The high risk of neonatal death from sepsis is thought to result from impaired responses by innate immune cells; however, the clinical observation of hyperinflammatory courses of neonatal sepsis contradicts this concept. Using transcriptomic, epigenetic and immunological approaches, we demonstrated that high amounts of the perinatal alarmins S100A8 and S100A9 specifically altered MyD88-dependent proinflammatory gene programs. S100 programming prevented hyperinflammatory responses without impairing pathogen defense. TRIF-adaptor-dependent regulatory genes remained unaffected by perinatal S100 programming and responded strongly to lipopolysaccharide, but were barely expressed. Steady-state expression of TRIF-dependent genes increased only gradually during the first year of life in human neonates, shifting immune regulation toward the adult phenotype. Disruption of this critical sequence of transient alarmin programming and subsequent reprogramming of regulatory pathways increased the risk of hyperinflammation and sepsis. Collectively these data suggest that neonates are characterized by a selective, transient microbial unresponsiveness that prevents harmful hyperinflammation in the delicate neonate while allowing for sufficient immunological protection.
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http://dx.doi.org/10.1038/ni.3745DOI Listing
June 2017

In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock.

FASEB J 2017 03 19;31(3):1153-1164. Epub 2016 Dec 19.

Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany;

The high susceptibility of newborn infants to sepsis is ascribed to an immaturity of the neonatal immune system, but the molecular mechanisms remain unclear. Newborn monocytes massively release the alarmins S100A8/S100A9. In adults, these are major regulators of immunosuppressive myeloid-derived suppressor cells (MDSCs). We investigated whether S100A8/S100A9 cause an expansion of monocytic MDSCs (Mo-MDSCs) in neonates, thereby contributing to an immunocompromised state. Mo-MDSCs have been assigned to CD14/human leukocyte antigen (HLA)-DR/CD33 monocytes in humans and to CD11b/Gr-1/Ly6G/Ly6C cells in mice. We found monocytes with these phenotypes significantly expanded in their respective newborns. Functionally, however, they did not prove immunosuppressive but rather responded inflammatorily to microbial stimulation. Their expansion did not correlate with high S100A8/S100A9 levels in cord blood. Murine studies revealed an excessive expansion of CD11b/Gr-1/Ly6G/Ly6C monocytes in S100A9 neonates compared to wild-type neonates. This strong baseline expansion was associated with hyperinflammatory responses during endotoxemia and fatal septic courses. Treating S100A9 neonates directly after birth with S100A8/S100A9 alarmins prevented excessive expansion of this inflammatory monocyte population and death from septic shock. Our data suggest that a specific population of inflammatory monocytes promotes fatal courses of sepsis in neonates if its expansion is not regulated by S100A8/S100A9 alarmins.-Heinemann, A. S., Pirr, S., Fehlhaber, B., Mellinger, L., Burgmann, J., Busse, M., Ginzel, M., Friesenhagen, J., von Köckritz-Blickwede, M., Ulas, T., von Kaisenberg, C. S., Roth, J., Vogl, T., Viemann, D. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock.
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http://dx.doi.org/10.1096/fj.201601083RDOI Listing
March 2017

Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy.

Basic Res Cardiol 2015 Nov 30;110(6):60. Epub 2015 Oct 30.

Department of Cardiology and Angiology, Hannover Medial School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Peripartum cardiomyopathy (PPCM) is a major cause of pregnancy-related maternal heart failure that develops towards the end of pregnancy or in the months following delivery. In small retrospective case series, autoimmune responses in the pathogenesis of PPCM have been proposed upon identification of autoantibodies (AABs) to cardiac antigens. However, their clinical and prognostic relevance still remain unclear. In this study, we evaluated the presence of circulating AABs against cardiac sarcomeric myosin (MHC) and troponin I (TnI) in the sera of PPCM patients and in relation to clinical presentation. In this case-control study, 70 patients diagnosed with PPCM and 50 pregnancy-matched healthy women with normal cardiac function were enrolled. Clinical assessment, echocardiography and blood tests were performed at baseline and at 6 ± 2 months follow-up. The presence of serum AABs against MHC (anti-MHC) and TnI (anti-TnI) was determined with a custom-made enzyme-linked immunosorbent assay (ELISA). The seropositivity for these AABs was correlated with the severity of LV dysfunction and the occurrence of pericardial effusion indicative of perimyocardial inflammation at baseline. Potential impact of these AABs on disease progression was evaluated with regard to functional (left ventricular ejection fraction) and clinical improvement at follow-up. Either anti-MHC or anti-TnI or both AABs were detected in the serum of 46 % of PPCM patients and in 8 % of healthy controls. In PPCM the presence of either one of these AABs was associated with significantly lower baseline LVEF and lower rate of full cardiac recovery at follow-up. Patients who were seropositive for anti-TnI AABs showed more frequently pericardial effusion indicative of a more pronounced immune response of the peri-/myocardium in these patients. Further studies are required to clarify cellular and molecular circuits leading to elevated levels of AABs and their pathophysiological relevance for disease initiation and progression in PPCM.
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http://dx.doi.org/10.1007/s00395-015-0517-2DOI Listing
November 2015

Successful Pregnancy and Neobladder Subsequent to Muscle Invasive Bladder Cancer and Fertility Preserving Surgery: Case Report and Review of the Literature.

Urol Int 2016 30;96(4):488-91. Epub 2015 May 30.

Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.

We report a successful pregnancy and birth subsequent to fertility-preserving cystectomy and neobladder formation in a muscle-invasive sarcomatoid urothelial carcinoma.
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http://dx.doi.org/10.1159/000430921DOI Listing
March 2017

Alarmins MRP8 and MRP14 induce stress tolerance in phagocytes under sterile inflammatory conditions.

Cell Rep 2014 Dec 11;9(6):2112-23. Epub 2014 Dec 11.

Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany.

Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14(-/-) mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation.
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http://dx.doi.org/10.1016/j.celrep.2014.11.020DOI Listing
December 2014

Hypoxia and the anticoagulants dalteparin and acetylsalicylic acid affect human placental amino acid transport.

PLoS One 2014 5;9(6):e99217. Epub 2014 Jun 5.

Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.

Background: Anticoagulants, e.g. low-molecular weight heparins (LMWHs) and acetylsalicylic acid (ASA) are prescribed to women at risk for pregnancy complications that are associated with impaired placentation and placental hypoxia. Beyond their role as anticoagulants these compounds exhibit direct effects on trophoblast but their impact on placental function is unknown. The amino acid transport systems A and L, which preferably transfer essential amino acids, are well-described models to study placental nutrient transport. We aimed to examine the effect of hypoxia, LMWHs and ASA on the activity of the placental amino acid transport systems A and L and associated signalling mechanisms.

Methods: The uptake of C14-MeAIB (system A) or H3-leucin (system L) was investigated after incubation of primary villous fragments isolated from term placentas. Villous tissue was incubated at 2% O2 (hypoxia), 8% O2 and standard culture conditions (21% O2) or at 2% O2 and 21% O2 with dalteparin or ASA. Activation of the JAK/STAT or mTOR signalling pathways was determined by Western analysis of total and phosphorylated STAT3 or Raptor.

Results: Hypoxia decreased system A mediated MeAIB uptake and increased system L mediated leucine uptake compared to standard culture conditions (21% O2). This was accompanied by an impairment of STAT3 and a stimulation of Raptor signalling. System L activity increased at 8% O2. Dalteparin treatment reduced system A and system L activity under normoxic conditions and ASA (1 mM) decreased system A and L transporter activity under normoxic and hypoxic conditions.

Conclusions: Our data underline the dependency of placental function on oxygen supply. LMWHs and ASA are not able to reverse the effects of hypoxia on placental amino acid transport. These findings and the uncovering of the signalling mechanisms in more detail will help to understand the impact of LMWHs and ASA on placental function and fetal growth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099217PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047053PMC
October 2015

Vitamin D prevents endothelial progenitor cell dysfunction induced by sera from women with preeclampsia or conditioned media from hypoxic placenta.

PLoS One 2014 2;9(6):e98527. Epub 2014 Jun 2.

Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.

Context: Placenta-derived circulating factors contribute to the maternal endothelial dysfunction underlying preeclampsia. Endothelial colony forming cells (ECFC), a sub-population of endothelial progenitor cells (EPCs), are thought to be involved in vasculogenesis and endothelial repair. Low vitamin D concentrations are associated with an increased risk for preeclampsia.

Objective: We hypothesized that the function of human fetal ECFCs in culture would be suppressed by exposure to preeclampsia-related factors--preeclampsia serum or hypoxic placental conditioned medium--in a fashion reversed by vitamin D.

Design, Setting, Patients: ECFCs were isolated from cord blood of uncomplicated pregnancies and expanded in culture. Uncomplicated pregnancy villous placenta in explant culture were exposed to either 2% (hypoxic), 8% (normoxic) or 21% (hyperoxic) O2 for 48 h, after which the conditioned media (CM) was collected.

Outcome Measures: ECFC tubule formation (Matrigel assay) and migration were examined in the presence of either maternal serum from preeclampsia cases or uncomplicated pregnancy controls, or pooled CM, in the presence or absence of 1,25(OH)2 vitamin D3.

Results: 1,25(OH)2 vitamin D3 reversed the adverse effects of preeclampsia serum or CM from hypoxic placenta on ECFCs capillary-tube formation and migration. Silencing of VDR expression by VDR siRNA, VDR blockade, or VEGF pathway blockade reduced ECFC functional abilities. Effects of VDR or VEGF blockade were partially prevented by vitamin D.

Conclusion: Vitamin D promotes the capillary-like tubule formation and migration of ECFCs in culture, minimizing the negative effects of exposure to preeclampsia-related factors. Further evaluation of the role of vitamin D in ECFC regulation and preeclampsia is warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098527PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041729PMC
January 2015

Analysis of SYCP3 encoding synaptonemal complex protein 3 in human aneuploidies.

Arch Gynecol Obstet 2013 Nov 16;288(5):1153-8. Epub 2013 May 16.

Institute of Human Genetics, University Hospital RWTH Aachen, 52074, Aachen, Germany.

Objectives: To test the hypothesis that mutations of SYCP3 encoding synaptonemal complex protein 3, result in increased frequency of aneuploidies in humans.

Methods: Mutation analysis of the PCR-amplified 8 coding exons and exon-intron boundaries of the SYCP3 gene was done by direct sequencing of DNA isolated from 35 aneuploid fetuses of women having a potentially increased likelihood for an underlying genetic predisposition for chromosomal non-disjunction.

Results: Based on the results of conventional karyotyping, the 35 aneuploid fetuses of 33 women were divided into separate groups: 9 aneuploid conceptuses of couples with recurrent aneuploid conceptions (4 of the women 35 years or younger), 12 conceptuses with double/multiple aneuploidies (5 of the women 35 years or younger), and 14 conceptuses with single aneuploidies of women younger than 35 years (8 trisomies and 6 monosomies). No pathogenic mutations in the SYCP3 coding exons and the immediately flanking intronic sequences were found.

Conclusions: Under the assumption that genetic predisposition for chromosomal non-disjunction leading to aneuploidy is most likely polygenic in nature, our data suggest that SYCP3 mutations are not one of the common causes in humans.
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http://dx.doi.org/10.1007/s00404-013-2861-5DOI Listing
November 2013

Preeclampsia and long-term risk of cardiovascular disease: what do obstetrician-gynecologists know?

BMC Pregnancy Childbirth 2013 Mar 9;13:61. Epub 2013 Mar 9.

Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str, 1, Hannover, 30625, Germany.

Background: Preeclampsia (PE), a hypertensive disorder of pregnancy affects 2-8% of women and is associated with increased cardiovascular disease (CVD) risk later in life. There is little information about the knowledge of obstetrician-gynecologists in German outpatient care setting regarding the future health risk of PE and knowledge of the current guidelines on treatment and counseling patients post PE. This study aimed to assess whether obstetrician-gynecologists are aware of PE's association with maternal long-term adverse outcomes and providing appropriate counseling.

Methods: A random sample of 500 obstetrician-gynecologists in the federal state of Lower Saxony was mailed a survey and a reminder with a second copy of the survey. The questionnaire elicited both personal information, and knowledge on future disease risks, e.g. cardiovascular disease (CVD) and current guidelines as well as on counseling practice. Descriptive analysis was used to analyze the responses.

Results: A total of 212 obstetrician-gynecologists (42.4%) responded to the questionnaire. A large proportion of physicians stated that PE was associated with a higher risk for the development for hypertension (86.6%), stroke (78.5%) and kidney disease (78.0%). Of the participants 75.8% reported that women after PE have a shorter life expectancy. Respondents with knowledge of the current guidelines of the German Association of Obstetrics and Gynecology concerning follow up and risk management of PE (45.2%) were more often aware of the development of CVD and stroke and counseled patients on self -blood-pressure measurement, meaning and long-term-risks of PE and attached importance to family history of PE compared to physicians with no knowledge of the guidelines.

Conclusion: Although the majority of obstetrician-gynecologists were aware of higher CVD risk after PE, weaknesses exist in the follow up care and counseling of these patients. These deficiencies would be amendable to directed educational activities to improve the implementation of current guidelines.
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http://dx.doi.org/10.1186/1471-2393-13-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605330PMC
March 2013

Diagnostic challenges of hemihematocolpos and dysmenorrhea in adolescents: obstructed hemivagina, didelphys or bicornuate uterus and renal aplasia is a rare female genital malformation.

Arch Gynecol Obstet 2012 Sep 5;286(3):785-91. Epub 2012 Jun 5.

Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Objectives: To develop a clear diagnostic and therapeutic strategy for adolescents presenting with abdominal pain and vaginal tumor caused by congenital female genital anomalies, such as blind hemivagina and uterine anomalies, as the lack of the correct diagnosis of the underlying anatomical genitourinary malformation frequently leads to destructive surgical procedures.

Methods: Retrospective study, study group: patients with double/bicornuate uterus, blind hemivagina and hematocolpos (n = 13), controls: patients with uterine malformation and complete vertical vaginal septum (n = 11), analysis for: menarche, age at onset of symptoms, type of malformation, symptoms leading to admission and diagnostic/surgical techniques applied.

Results: Median age at diagnosis study group 19.85 (SD ± 6.23, range 13-23 years) versus controls 26.09 years (SD ± 7.44, 16-36 years); predominance of imperforated hemivagina: 69.2 % right-sided versus 30.8 % left-sided septum; renal agenesis ipsilateral to imperforate hemivagina 100 % study group versus 9.1 % controls; 84.6 % previous surgical interventions in the study group, such as partial removal of the septum and re-obliteration, unilateral salpingo-ovarectomy and vaginal drainage of pyometra. We used a single transvaginal surgical procedure, including removal of the obstructed vaginal septum and marsupialization of the blind hemivagina.

Conclusions: A diagnostic and therapeutic algorithm for young women presenting with progressive dysmenorrhea and abdominal pain and/or vaginal tumor reduces destructive interventions.
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http://dx.doi.org/10.1007/s00404-012-2392-5DOI Listing
September 2012

Chromosomal mosaicisms in prenatal diagnosis: correlation with first trimester screening and clinical outcome.

J Perinat Med 2012 Jan 6;40(3):215-23. Epub 2012 Jan 6.

Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Kiel and Christian-Albrechts-University Kiel, Kiel, Germany.

Objective: To investigate the outcome of pregnancy after detection of chromosomal mosaicism and to determine the correlation between human chorionic gonadotropin (free β-HCG) and pregnancy-associated plasma protein-A (PAPP-A) levels from first-trimester-screening with pregnancy outcome.

Methods: In a single-center, retrospective survey of the results of prenatal diagnostics performed between January 2000 and March 2011, we identified a total of 40 pregnancies with chromosomal mosaicism. Clinical characteristics and results of first-trimester screening, as well as the outcome of these cases, are described.

Results: Out of 40 cases, 21 were defined as confined placental mosaicism, 10 classified as true mosaicism and nine were not classifiable cases. Nuchal translucency (NT) was ≥2.5 mm in 8/30 cases with respective measurements. PAPP-A levels were ≤0.4 MoM in 9/26 cases, with respective measurements, two of them being newborns with growth restriction. Remarkably, in pregnancies of all four children born with severe growth retardation, <3rd percentile PAPP-A levels were below 0.52 MoM.

Conclusions: Our observations show mosaic pregnancy outcomes to be very heterogeneous. Nevertheless, a combination of low PAPP-A and interpretation of chromosomal mosaicism might identify pregnancies at particular risk for fetal growth restriction.
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http://dx.doi.org/10.1515/jpm.2011.130DOI Listing
January 2012

Pathologic ultrasound findings and risk for congenital anomalies in teenage pregnancies.

J Matern Fetal Neonatal Med 2012 Oct 24;25(10):1950-2. Epub 2012 Apr 24.

Department of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Campus Kiel, Germany.

Objective: To detect the number and diagnosis of fetal malformations in teenage pregnancies and to evaluate whether low maternal age or epigenetic factors have an influence on this issue.

Materials And Methods: We performed a retrospective analysis in a single center for prenatal diagnostics in Northern Germany. We searched our electronic databank for all pregnancies with maternal age under 20 years. Pregnancy outcome and fetal malformations are described.

Results: The incidence of teenage pregnancies in our study was 638 patients (4.4%). The total of fetal malformations in teenage pregnancies was 51(8.3%). Chromosomal aberrations were found in 5 cases (0.9%). 9 cases of fetal gastroschisis as one of the most frequent malformations were followed up and neonatal outcome was uneventful. Furthermore we found 16 cases with different heart defects and 30 cases with other malformations. Patients' body mass indices showed an increase over the years and nicotine consumption was testified in more than 50% of the patients.

Conclusions: Teenage pregnancies are at risk for fetal non-chromosomal and chromosomal abnormalities. As these might be detected by first-trimester-screening prenatal care in teenage pregnancies should include at least early ultrasound examination. Epigenetic factors may play a key role in certain fetal malformations.
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http://dx.doi.org/10.3109/14767058.2012.678436DOI Listing
October 2012

Isolated trisomy 7q21.2-31.31 resulting from a complex familial rearrangement involving chromosomes 7, 9 and 10.

Mol Cytogenet 2011 Dec 5;4:28. Epub 2011 Dec 5.

Institute of Human Genetics, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str.3, Haus 10, Kiel, Germany.

Background: Genotype-phenotype correlations for chromosomal imbalances are often limited by overlapping effects of partial trisomy and monosomy resulting from unbalanced translocations and by poor resolution of banding analysis for breakpoint designation. Here we report the clinical features of isolated partial trisomy 7q21.2 to 7q31.31 without overlapping phenotypic effects of partial monosomy in an 8 years old girl. The breakpoints of the unbalanced rearranged chromosome 7 could be defined precisely by array-CGH and a further imbalance could be excluded. The breakpoints of the balanced rearranged chromosomes 9 and 10 were identified by microdissection of fluorescence labelled derivative chromosomes 9 and 10.

Results: The proband's mother showed a complex balanced translocation t(9;10)(p13;q23) with insertion of 7q21.2-31.31 at the translocation breakpoint at 9p13. The daughter inherited the rearranged chromosomes 9 and 10 but the normal chromosome 7 from her mother, resulting in partial trisomy 7q21.2 to 7q31.31. The phenotype of the patient consisted of marked developmental retardation, facial dysmorphism, short stature, strabism, and hyperextensible metacarpophalangeal joints.

Discussion: For better understanding of genotype-phenotype correlation a new classification of 7q duplications which will be based on findings of molecular karyotyping is needed. Therefore, the description of well-defined patients is valuable. This case shows that FISH-microdissection is of great benefit for precise breakpoint designation in balanced rearrangements.
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http://dx.doi.org/10.1186/1755-8166-4-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261807PMC
December 2011

Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines.

J Cancer Res Clin Oncol 2011 May 29;137(5):875-86. Epub 2010 Sep 29.

Department of Gynecology and Obstetrics, University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.

Purpose: Ovarian cancer accounts for the highest mortality among all gynecological cancers, mainly due to the fast developing chemoresistance. The death ligand TRAIL induces apoptosis and is able to sensitize tumor cells to cytostatic drugs without affecting physiological tissue. Combined treatment of TRAIL and the antidiabetic acting PPARγ ligands was shown to induce apoptosis synergistically in different ovarian cancer cell lines.

Methods: To investigate feasible TRAIL-dependent inhibition of proliferation and induction of apoptosis in chemoresistant ovarian cancer cell lines, the drug- and TRAIL-sensitive HEY cell line was utilized to develop subclones with selective resistance against cisplatin, etoposide, docetaxel, paclitaxel, gemcitabine and pemetrexed, as well as against TRAIL as control cell line. Expression of the key factors of the TRAIL signaling pathway, TRAIL receptors 1-4, caspase-8, FLIP and XIAP, was analyzed before and after TRAIL treatment by immunoblotting.

Results: Cell proliferation experiments showed TRAIL-dependent inhibition that was further increased by combination treatment with the PPARγ ligands. Simultaneous exposure of TRAIL and the PPARγ ligands also resulted in enhanced induction of apoptosis even in partial TRAIL-resistant HEY cell lines. In the parental HEY cell line, additional treatment with the PPARγ ligands led to an increased protein expression of DR5 and a further decline of XIAP expression.

Conclusion: Therefore, the combinational treatment with TRAIL and PPARγ ligands might be a promising experimental therapy because the PPARγ ligands, especially d15-PGJ(2), sensitize drug-resistant ovarian cancer cells to TRAIL-induced apoptosis.
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http://dx.doi.org/10.1007/s00432-010-0952-2DOI Listing
May 2011

Biochemical tissue-specific injury markers of the heart and brain in postpartum cord blood.

Am J Obstet Gynecol 2009 Mar 24;200(3):273.e1-273.e25. Epub 2009 Jan 24.

Department of Obstetrics and Gynecology, Poznan University of Medical Sciences, Poznan, Poland.

Objective: We sought to establish references ranges and to test the hypothesis that biochemical tissue-specific markers for the heart in umbilical cord blood of newborns with cardiac defects and intrauterine growth restriction (IUGR) are abnormal.

Study Design: A prospective study was conducted. Serum samples of the umbilical vein (n = 280) and artery (n = 156) from 599 healthy newborns at 37(+0)-42(+0) weeks of gestation were collected. Total creatine kinase (CK), CK-MB heart type (CK-MB), cardiac troponin T (cTnT), myoglobin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and S100 were measured. Reference ranges for each marker were constructed. Concentrations of tissue-specific markers from umbilical cord blood of neonates with cardiac defects (n = 10) and IUGR (n = 41) were plotted against the established reference ranges.

Results: Reference ranges for each studied marker were established for both umbilical artery and vein. In fetuses with cardiac defects, both NT-proBNP (4/6 [66%] in the artery, 7/10 [70%] in the vein) and cTnT (2/10 [20%] in the vein) were increased. In fetuses with IUGR in the vein, NT-proBNP (10/41 [24%]) and cTnT (5/41 [12%]) were increased, whereas S100 (9/41 [21%]) was decreased.

Conclusion: In a subset of neonates with cardiac defects or growth restriction, irrespective of the pH at birth, tissue-specific injury markers for the heart in umbilical cord blood are abnormal.
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http://dx.doi.org/10.1016/j.ajog.2008.10.009DOI Listing
March 2009

Congenital diaphragmatic hernia, etiology and management, a 10-year analysis of a single center.

Arch Gynecol Obstet 2008 Jan 7;277(1):55-63. Epub 2007 Aug 7.

Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Campus Kiel, Michaelisstrasse 16, Kiel, Germany.

Objective: To analyze congenital diaphragmatic hernia (CDH) during a 10-year period at the University of Kiel, from 1995 through 2004, in order to develop a strategy to improve prenatal diagnosis, to be able to consider endoscopical treatment for selected cases and to assess the current postnatal treatment strategies.

Methods: Data were obtained from the fetal medicine ultrasound department, from the birth registry, from the postmortem registry, from the neonatal intensive care unit, from pediatric surgery and from the genetic database. Data were subselected for chromosomes, genetic syndromes, for isolated CDH and for associated anomalies, the lung to head ratio and lung volumes were assessed. Data were analyzed respectively for gestation at diagnosis, the type of CDH, the perinatal management and the postnatal outcome.

Results: There were 29 cases of CDH, in 10/29 (34%) the parents requested termination of pregnancy of which two had already died during pregnancy, 12/19 (63%) survived, which was defined as discharge from the neonatal intensive care unit, seven newborns 7/19 (37%) died in the hospital, 5 of these 5/7 (71%) were delivered in Kiel. A prenatal diagnosis was performed in 16/29 (55%), 1/16 (6%), 7/16 (43%) and 8/16 (50%) in the 1st, 2nd and 3rd trimester, respectively; in 10/29 (34%) diagnosis was performed postpartum, in 3/29 (10%) the diagnosis was performed at autopsy following termination of pregnancy. When the liver was in the abdomen, 9/10 (90%) of the children survived, compared to only 3/8 (43%) when the liver was located in the thorax. A lung to head ratio of 0.81 at 24 weeks resulted in death due to pulmonary hypoplasia.

Conclusions: The overall survival in CDH is around 50%, antenatal endoscopical therapy may only be considered, if the diagnosis is performed in the early second trimester, and selection criteria such as the lung to head ratio, associated defects and the chromosomal status can be applied.
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http://dx.doi.org/10.1007/s00404-007-0407-4DOI Listing
January 2008

Successful intrauterine intracardiac transfusion in monochorionic twins affected by parvovirus B19.

Fetal Diagn Ther 2007 24;22(6):420-4. Epub 2007 Jul 24.

Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Objectives: To assess the possibility to correct for fetal anemia using an intracardiac approach in twin pregnancies affected by fetal Parvovirus B19 infection.

Methods: A monochorionic twin pregnancy affected by fetal Parvovirus B19 infection and hydrops was treated using an intraabdominal approach and by intracardiac transfusions. Access to the umbilical cord was not possible.

Results: In one fetus, hydrops resolved after intraabdominal transfusions, in the other however, hydrops was progressive. After intracardiac transfusions, both fetuses normalized.

Conclusions: In multiple gestation affected by anemia, intracardiac transfusion is a possible and alternative technique, if access to the cord is impossible.
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http://dx.doi.org/10.1159/000106346DOI Listing
December 2007

An integrated clinical-genomics approach identifies a candidate multi-analyte blood test for serous ovarian carcinoma.

Clin Cancer Res 2007 Jan;13(2 Pt 1):458-66

Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany.

Purpose: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood.

Experimental Design: We developed an algorithm to identify secreted proteins encoded among approximately 22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression.

Results: We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (<0.5- or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls.

Conclusions: Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-0691DOI Listing
January 2007

Ovarian surgery and follicular reserve.

Expert Rev Endocrinol Metab 2006 Nov;1(6):743-752

a Professor, University Hospitals Schleswig-Holstein, Campus Kiel, Department of Obstetrics and Gynecology, Michaelisstr. 16, 24105 Kiel, Germany.

In patients with cystic ovarian pathology, such as endometriomas, polycystic ovary syndrome, teratomas or benign tumors, there is a tendency towards abnormal ovarian function. Anovulation and sterility may occur. This review will summarize the normal physiology of the female gonad and the development of oogenesis from initial reproductive age to the menopause. Furthermore, the interaction between ovarian pathology and endocrinology will be described. The main focus is on the technique of ovarian-preserving surgery by laparoscopy. In addition, alternative therapeutic approaches and screening tests will be discussed.
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http://dx.doi.org/10.1586/17446651.1.6.743DOI Listing
November 2006

Reversed pulmonary artery flow in isolated noncompaction of the ventricular myocardium.

Fetal Diagn Ther 2007 21;22(1):29-32. Epub 2006 Sep 21.

Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Objective: To investigate the morphology and genetics of a fetus at 22 weeks. This fetus demonstrated progressive fetal hydrops and cardiomegaly with retrograde flow in the pulmonary artery and progressive myocardial deterioration and heart failure.

Methods: Postmortem examination, light and electron microscopy of the myocardium, karyotyping, fetal DNA analysis, screening for mutations in the G4.5 gene, alpha-dystrobrevin gene, FKBP 12 gene, Desmin, Syntrophin and Cypher/ZASP genes, which have been described as being associated with noncompaction ventricular myocardium, using single-strand DNA conformation polymorphism analysis and DNA sequencing.

Results: The morphological diagnosis was compatible with noncompaction ventricular myocardium or spongyforme myopathy. The karyotype was normal. Mutation analysis in exons and introns of all six genes did not show any known mutation.

Conclusion: Noncompaction ventricular myocardium or spongyforme myopathy may be associated with mutations in genes which have previously not been thought to be associated with this phenotype. Alternatively, this disease could be the result of abnormal cardiac hemodynamics.
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http://dx.doi.org/10.1159/000095839DOI Listing
February 2007

Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos.

Dev Dyn 2006 Jun;235(6):1554-62

Children's Hospital, Pediatrics I, University of Goettingen, Goettingen, Germany.

The development of lymphatic endothelial cells (LECs) from deep embryonic veins or mesenchymal lymphangioblasts is controversially discussed. Studies employing quail-chick grafting experiments have shown that various mesodermal compartments of the embryo possess lymphangiogenic potential, whereas studies on murine embryos have been in favor of a venous origin of LECs. We have investigated NMRI mice from embryonic day (ED) 9.5 to 13.5 with antibodies against the leukocyte marker CD45, the pan-endothelial marker CD31, and the lymphendothelial markers Prox1 and Lyve-1. Early signs of the development of lymphatics are the Lyve-1- and Prox1-positive segments of the jugular and vitelline veins. Then, lymph sacs, which are found in the jugular region of ED 11.5 mice, express Prox1, Lyve-1, and CD31. Furthermore, scattered cells positive for all of the four markers are present in the mesenchyme of the dermatomes and the mediastinum before lymphatic vessels are present in these regions. Their number increases during development. A gradient of increasing CD31 expression can be seen the closer the cells are located to the lymph sacs. Our studies provide evidence for the existence of scattered mesenchymal cells, which up-regulate lymphendothelial and down-regulate leukocyte characteristics when they integrate into growing murine lymphatics. Such stem cells may also be present in the human and may be the cell of origin in post-transplantation Kaposi sarcoma.
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http://dx.doi.org/10.1002/dvdy.20737DOI Listing
June 2006