Wolfgang Eppel

Human papillomavirus in the cervix and placenta.

Objective To determine the prevalence and association of human papillomavirus (HPV) infection in the cervices and placentas of pregnant women. Methods Cervical samples were taken from 179 of 226 women who had placental biopsies because of abnormal ultrasound findings or were older than 35 years, to detect HPV infections with hybrid capture II tests. Polymerase chain reaction (PCR) was done on placental tissue of 147 of the 226 women to detect HPV DNA. Results We found 44 of 179 women (24.6%, 95% confidence interval 18.3, 31.0) to test positive for HPV in their cervices. Logistic regression analyses showed decreased prevalence of HPV infection with increased maternal age (P = .039). The HPV DNA E6 PCR from the villus tissue was negative in the 147 cases examined. However, a significant contingency coefficient between low-risk HPV infection and elevated risk of chromosome aberration was found (&phis; = V = 0.15, P = .050). Conclusion The infection rate of 24.6% in women without clinical symptoms of HPV infection was high, but there seemed to be no virus transmission to the placenta in women with subclinical infections. Low-risk cervical HPV infection might be associated with a slightly higher risk of abnormal fetal karyotype.

HLA-DR+ leukocytes acquire CD1 antigens in embryonic and fetal human skin and contain functional antigen-presenting cells

Adequate numbers and functional maturity are needed for leukocytes to exhibit a protective role in host defense. During intrauterine life, the skin immune system has to acquire these prerequisites to protect the newborn from infection in the hostile external environment after birth. We investigated the quantitative, phenotypic, and functional development of skin leukocytes and analyzed the factors controlling their proliferation and trafficking during skin development. We show that CD45+ leukocytes are scattered in embryonic human skin and that their numbers continuously increase as the developing skin generates an environment that promotes proliferation of skin resident leukocytes as well as the influx of leukocytes from the circulation. We also found that CD45+HLA-DRhighCD1c+ dendritic cells (DCs) are already present in the epidermis and dermis at 9 wk estimated gestational age (EGA) and that transforming growth factor β1 production precedes Langerin and CD1a expression on CD45+CD1c+ Langerhans cell (LC) precursors. Functionally, embryonic antigen-presenting cells (APCs) are able to phagocytose antigen, to up-regulate costimulatory molecules upon culture, and to efficiently stimulate T cells in a mixed lymphocyte reaction. Collectively, our data provide insight into skin DC biology and the mechanisms through which skin DCs presumably populate the skin during development.

Fetal fibronectin as a marker to predict the onset of term labor and delivery

OBJECTIVEnWe examined whether the presence of fetal fibronectin in cervicovaginal secretions may be a marker to predict the onset of term labor and delivery.nnnSTUDY DESIGNnA prospective study was performed in 100 primiparous and multiparous women having reached their expected date of confinement. Fetal fibronectin was assayed by taking samples of both the cervical and vaginal mucus with two different fetal fibronectin tests. The study population was divided into women delivering within 48 hours and women giving birth > 48 hours after sampling.nnnRESULTSnSeven patients had to be excluded from evaluation. Of the remaining 93 women, 37 were delivered within 48 hours; fetal fibronectin was detected in 30. Fifty-six women were delivered later than 48 hours; 51 of them had negative results for fetal fibronectin (positive accuracy 86%, negative accuracy 88%, p < 0.0001).nnnCONCLUSIONnFetal fibronectin in the cervicovaginal secretions of women who have reached their expected date of confinement is a useful predictor of the onset of term labor and delivery.

Prevalence of Cervical and Intrauterine Human Papillomavirus Infected in the Third Trimester in Asymptomatic Women

Objective: To study the prevalence and association of human papillomavirus (HPV) infection in the cervix of pregnant women without visible signs of genital HPV infection undergoing cesarean delivery in the third trimester and to investigate a possible HPV transmission to the fetus. Methods: All women underwent cesarean delivery between 37 and 40 weeks of gestation. Cervical samples were taken prior to cesarean delivery. Furthermore, amniotic fluid, placental tissue, and cord blood were sampled and polymerase chain reaction (PCR) or Hybrid Capture II test (Digene Corp, Beltsville, MD) was performed to detect HPV DNA. Results: We found that 56 (36.6%) of 153 women were positive for HPV in the cervix. Logistic regression analyses showed a decrease of prevalence of HPV infection with increasing maternal age (P = .02). No HPV DNA could be detected in the amniotic fluid or cord blood, whereas eight placental specimens were positive for HPV DNA. Conclusion: The infection rate in women without clinical symptoms of HPV infection is high, but there was no HPV found in the amniotic fluid and in cord blood in women with subclinical infection in the third trimester.

Tissue factor is induced by interleukin-33 in human endothelial cells: a new link between coagulation and inflammation.

Tissue factor (TF) is the primary trigger of coagulation. Elevated levels of TF are found in atherosclerotic plaques, and TF leads to thrombus formation when released upon plaque rupture. Interleukin (IL)-33 was previously shown to induce angiogenesis and inflammatory activation of endothelial cells (ECs). Here, we investigated the impact of IL-33 on TF in human ECs, as a possible new link between inflammation and coagulation. IL-33 induced TF mRNA and protein in human umbilical vein ECs and coronary artery ECs. IL-33-induced TF expression was ST2- and NF-κB-dependent, but IL-1-independent. IL-33 also increased cell surface TF activity in ECs and TF activity in ECs-derived microparticles. IL-33-treated ECs reduced coagulation time of whole blood and plasma but not of factor VII-deficient plasma. In human carotid atherosclerotic plaques (nu2009=u200957), TF mRNA positively correlated with IL-33 mRNA expression (ru2009=u20090.691, pu2009<u20090.001). In this tissue, IL-33 and TF protein was detected in ECs and smooth muscle cells by immunofluorescence. Furthermore, IL-33 and TF protein co-localized at the site of clot formation within microvessels in plaques of patients with symptomatic carotid stenosis. Through induction of TF in ECs, IL-33 could enhance their thrombotic capacity and thereby might impact on thrombus formation in the setting of atherosclerosis.

Phenotypic Characterization of Leukocytes in Prenatal Human Dermis

The adult human skin harbors a variety of leukocytes providing immune surveillance and host defense, but knowledge about their ontogeny is scarce. In this study we investigated the number and phenotype of leukocytes in prenatal human skin (dermal dendritic cells (DDCs), macrophages, T cells (including FoxP3+ regulatory T cells), and mast cells) to unravel their derivation and to get a clue as to their putative function in utero. By flow cytometry and immunofluorescence, we found a distinction between CD206+CD1c+CD11c+ DDCs and CD206+CD209+CD1c− skin macrophages by 9 weeks estimated gestational age (EGA). T cells appear at the end of the first trimester, expressing CD3 intracytoplasmatically. During midgestation, CD3+FoxP3− and CD3+FoxP3+ cells can exclusively be found in the dermis. Similarly, other leukocytes such as CD117+ (c-kit) mast cells were not identified before 12–14 weeks EGA and only slowly acquire a mature phenotype during gestation. Our data show at which time point during gestation antigen-presenting cells, T cells, and mast cells populate the human dermis and provide a step forward to a better understanding of the development of the human skin immune system.

Human embryonic epidermis contains a diverse Langerhans cell precursor pool

Despite intense efforts, the exact phenotype of the epidermal Langerhans cell (LC) precursors during human ontogeny has not been determined yet. These elusive precursors are believed to migrate into the embryonic skin and to express primitive surface markers, including CD36, but not typical LC markers such as CD1a, CD1c and CD207. The aim of this study was to further characterize the phenotype of LC precursors in human embryonic epidermis and to compare it with that of LCs in healthy adult skin. We found that epidermal leukocytes in first trimester human skin are negative for CD34 and heterogeneous with regard to the expression of CD1c, CD14 and CD36, thus contrasting the phenotypic uniformity of epidermal LCs in adult skin. These data indicate that LC precursors colonize the developing epidermis in an undifferentiated state, where they acquire the definitive LC marker profile with time. Using a human three-dimensional full-thickness skin model to mimic in vivo LC development, we found that FACS-sorted, CD207- cord blood-derived haematopoietic precursor cells resembling foetal LC precursors but not CD14+CD16- blood monocytes integrate into skin equivalents, and without additional exogenous cytokines give rise to cells that morphologically and phenotypically resemble LCs. Overall, it appears that CD14- haematopoietic precursors possess a much higher differentiation potential than CD14+ precursor cells.

Altered glucose profiles and risk for hypoglycaemia during oral glucose tolerance testing in pregnancies after gastric bypass surgery

Aims/hypothesisA history of gastric bypass surgery can influence the results of the OGTT recommended during pregnancy. Therefore, we compared OGTT glucose kinetics and pregnancy outcome between pregnant gastric bypass patients and BMI-matched, lean and obese controls.MethodsMedical records were used to collect data on glucose measurements during the 2xa0h 75xa0g OGTT as well as on pregnancy and fetal outcome for 304 women (nu2009=u200976 per group, matched for age and date of delivery).ResultsWomen after bariatric surgery had lower fasting glucose levels compared with lean, obese and BMI-matched controls, and showed altered postprandial glucose kinetics, including a rise at 60xa0min followed by hypoglycaemia with serum glucose of <3.34xa0mmol/l (which occurred in 54.8%). Moreover, their risk of pre-eclampsia or gestational hypertension was reduced, with an increased risk of delivering small for gestational age infants.Conclusions/interpretationAlternative strategies to accurately define impaired glucose metabolism in pregnancies after bariatric surgery should be explored.

Age intrinsic loss of telomere protection via TRF1 reduction in endothelial cells

Aging is a major factor predisposing for multiple diseases. Telomeres at the ends of chromosomes protect the integrity of chromosomal DNA. A specialized six-protein complex termed shelterin protects the telomere from unwanted interaction with DNA damage pathways. The aim of our study was to evaluate the integrity of telomeres and the stability of telomere protection during aging in endothelial cells (EC). We describe that aging EC can be characterized by an increased cell size (40%, p=0.02) and increased expression of PAI 1 (4 fold, p=0.02), MCP1 (10 fold, p=0.001) and GMCSF (15 fold, p=0.004). Telomeric state in aging cells is defined by an increased telomere oxidation (27%, p=0.01), reduced telomere length (62%, p=0.02), and increased DNA damage foci formation (5% in young EC versus 16% in aged EC, p=0.003). This telomeric dysfunction is accompanied by a reduction in the shelterin component TRF1 (33% mRNA, p=0.001; 24% protein, p=0.007). Overexpression of TRF1 in aging EC reduced telomere-associated DNA damage foci to 5% (p=0.02) and reduced expression levels of MCP1 (18% reduction, p=0.008). Aged EC have increased telomere damage and an intrinsic loss of telomere protection. Reestablishing telomere integrity could therefore be a target for rejuvenating endothelial cell function.

The influence of cotinine on interleukin 6 expression in smokers with cervical preneoplasia.

Background. Several epidemiological investigations have shown that cigarette smoking leads to increased serum IL‐6 levels and is a risk factor for cervical cancer.