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Pregnancy Close to the Edge: An Immunosuppressive Infiltrate in the Chorionic Plate of Placentas from Uncomplicated Egg Cell Donation
Dorrith Schonkeren, Godelieve Swings, Drucilla Roberts, Frans Claas, Emile de Heer, Sicco Scherjon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032347
Abstract: In pregnancies achieved after egg donation (ED) tolerance towards a completely allogeneic fetus is mediated by several complex immunoregulatory mechanisms, of which numerous aspects are still unknown. A distinct lesion not described previously in the literature, was repeatedly found in the chorionic plate in a substantial portion of placentas from ED pregnancies, but never in placentas from normal term pregnancies. The aim of this study was to assess its origin and its cellular composition. The relation between the lesion, the clinical and histological parameters were assessed. In addition we investigated the relation with the number of HLA-mismatches and KIR genotype of mother and child. In ten out of twenty-six (38.5%) placentas from ED pregnancies an inflammatory lesion was present in the chorionic plate. A significantly lower incidence of pre-eclampsia was found in the group with the lesion; 0% versus 45.5%. A significant relation was found between this lesion and the presence of intervillositis, chronic deciduitis, presence of plasma cells and fibrin deposition in the decidua. Fluorescent in situ hybridisation with X/Y-chromosome probes showed that the majority of cells present in the lesion are of maternal origin. The expression of the macrophage marker CD14+ and of the type 2 macrophage (M2) marker CD163+ was significantly higher in the lesion. The incidence of a fetal HLA-C2 genotype was significantly higher in cases with a lesion compared to the group without the lesion. In conclusion, a striking relationship was observed between the presence of a not previously described inflammatory lesion in the chorionic plate and the absence of pre-eclampsia in ED pregnancies. The lesion consists of mainly maternal cells with a higher expression of the macrophage marker CD14+ and the M2 marker CD163+. These findings suggest a protective immune mechanism which might contribute to the prevention of severe clinical complications like pre-eclampsia.
Increased incidence of pregnancy complications in women who later develop scleroderma: a case control study
Linda van Wyk, Jacolien van der Marel, Annemie JM Schuerwegh, Anne A Schouffoer, Alexandre E Voskuyl, Tom WJ Huizinga, Diana W Bianchi, Sicco A Scherjon
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3510
Abstract: This study was a retrospective multi-centre matched case-control study. One-hundred-and-three women with systemic sclerosis (SSc) and 103 women with no history of SSc or other autoimmune disease were given a questionnaire regarding complications during pregnancy, such as hypertension, intra-uterine growth restriction (IUGR) and miscarriage. Conditional logistic regression analysis was used to assess associations.We found a statistically significantly increased incidence of having had a pregnancy history of hypertension or a fetus with IUGR in women who subsequently developed SSc compared to healthy controls. We found an odds ratio of 2.6 (95% confidence interval (CI): 1.1 to 4.6) for hypertensive complications during pregnancy and an odds ratio of 3.9 (95% CI: 1.2 to 12.3) for intra-uterine growth restriction for women with SSc compared to healthy controls.This is the first study to show an association between hypertensive complications during pregnancy or IUGR and the development of SSc at a later age. We speculate that the pregnancy abnormalities may have resulted in increased fetomaternal trafficking, which may have played a role in the increased incidence of SSc. Further studies are indicated to examine this putative relationship.Systemic sclerosis (SSc) is a connective tissue disease of unknown origin that is characterized by cutaneous and visceral fibrosis, production of auto-antibodies, and prominent microvascular changes. The similarities of this autoimmune disease to graft versus host disease, which is an iatrogenic form of chimerism, have suggested a common pathway in the pathogenesis of both diseases [1].Increased trafficking of fetal cells into maternal circulation occurs with pregnancy complications such as preeclampsia [2-4]. In preeclampsia, deficient invasion of cytotrophoblasts results in insufficient modification of the maternal spiral arteries. This failure leads to placental hypoxia and placental lesions, which possibly result in increased traffi
Human Embryonic and Fetal Mesenchymal Stem Cells Differentiate toward Three Different Cardiac Lineages in Contrast to Their Adult Counterparts
Arti A. Ramkisoensing, Dani?l A. Pijnappels, Sa?d F. A. Askar, Robert Passier, Jim Swildens, Marie José Goumans, Cindy I. Schutte, Antoine A. F. de Vries, Sicco Scherjon, Christine L. Mummery, Martin J. Schalij, Douwe E. Atsma
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024164
Abstract: Mesenchymal stem cells (MSCs) show unexplained differences in differentiation potential. In this study, differentiation of human (h) MSCs derived from embryonic, fetal and adult sources toward cardiomyocytes, endothelial and smooth muscle cells was investigated. Labeled hMSCs derived from embryonic stem cells (hESC-MSCs), fetal umbilical cord, bone marrow, amniotic membrane and adult bone marrow and adipose tissue were co-cultured with neonatal rat cardiomyocytes (nrCMCs) or cardiac fibroblasts (nrCFBs) for 10 days, and also cultured under angiogenic conditions. Cardiomyogenesis was assessed by human-specific immunocytological analysis, whole-cell current-clamp recordings, human-specific qRT-PCR and optical mapping. After co-culture with nrCMCs, significantly more hESC-MSCs than fetal hMSCs stained positive for α-actinin, whereas adult hMSCs stained negative. Furthermore, functional cardiomyogenic differentiation, based on action potential recordings, was shown to occur, but not in adult hMSCs. Of all sources, hESC-MSCs expressed most cardiac-specific genes. hESC-MSCs and fetal hMSCs contained significantly higher basal levels of connexin43 than adult hMSCs and co-culture with nrCMCs increased expression. After co-culture with nrCFBs, hESC-MSCs and fetal hMSCs did not express α-actinin and connexin43 expression was decreased. Conduction velocity (CV) in co-cultures of nrCMCs and hESC-MSCs was significantly higher than in co-cultures with fetal or adult hMSCs. In angiogenesis bioassays, only hESC-MSCs and fetal hMSCs were able to form capillary-like structures, which stained for smooth muscle and endothelial cell markers.Human embryonic and fetal MSCs differentiate toward three different cardiac lineages, in contrast to adult MSCs. Cardiomyogenesis is determined by stimuli from the cellular microenvironment, where connexin43 may play an important role.
Fetal Mesenchymal Stromal Cells Differentiating towards Chondrocytes Acquire a Gene Expression Profile Resembling Human Growth Plate Cartilage
Sandy A. van Gool, Joyce A. M. Emons, Jeroen C. H. Leijten, Eva Decker, Carsten Sticht, Johannes C. van Houwelingen, Jelle J. Goeman, Carin Kleijburg, Sicco A. Scherjon, Norbert Gretz, Jan Maarten Wit, Gudrun Rappold, Janine N. Post, Marcel Karperien
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044561
Abstract: We used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFβ3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development.
Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial)
Jolande Y Vis, Femke F Wilms, Martijn A Oudijk, Martina M Porath, Hubertina CJ Scheepers, Kitty WM Bloemenkamp, Annemiek C Bolte, Jér?me Cornette, Jan B Derks, Johannes J Duvekot, Jim van Eyck, Anneke Kwee, Brent C Opmeer, Maria G van Pampus, Fred K Lotgering, Sicco A Scherjon, Krystyna M Sollie, Marc EA Spaanderman, Christine Willekes, Joris AM van der Post, Ben Mol
BMC Pregnancy and Childbirth , 2009, DOI: 10.1186/1471-2393-9-38
Abstract: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, β 0.2, α 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin.This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor.Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl webcite.Preterm birth is the most frequent cause of perinatal mortality and severe perinatal morbidity in the Western world [1]. Preterm birth can
Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial)
Carolien Roos, Liesbeth HCJ Scheepers, Kitty WM Bloemenkamp, Annemiek Bolte, Jerome Cornette, Jan B Derks, Hans JJ Duvekot, Jim van Eyck, Joke H Kok, Anneke Kwee, Ashley Merién, Brent C Opmeer, Mari?lle G van Pampus, Dimitri NM Papatsonis, Martina M Porath, Joris AM van der Post, Sicco A Scherjon, Krystyne Sollie, Marc EA Spaanderman, Sylvia MC Vijgen, Christine Willekes, Ben Mol, Fred K Lotgering
BMC Pregnancy and Childbirth , 2009, DOI: 10.1186/1471-2393-9-42
Abstract: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, β 0.2 at alpha 0.05).This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks.Clinical trial registration: http://www.trialregister.nl webcite, NTR 1336, date of registration: June 3rd 2008.Preterm birth is the most common cause of neonatal morbidity and death worldwide [1]. Two thirds of the preterm births occur as a result of spontaneous labour beginning with spontaneous contractions or with preterm rupture of membranes. Preterm birth accounts for approximately 75% of all neonatal deaths and 50% of childhood neurological morbidities [2]. Moreover, it is associated with high immediate and long-term costs after discharge from the hospital [3]. These include costs for special education services and institutionalised care for physically and mentally disabled infants [4]. The prevalence of adverse neonatal outcome is strongly related to gestational age at delivery and declines from 77% at 24-27 weeks to less then 2% at 34 weeks and
Disproportionate Intrauterine Growth Intervention Trial At Term: DIGITAT
Kim E Boers, Denise Bijlenga, Ben WJ Mol, Saskia LeCessie, Erwin Birnie, Marielle G van Pampus, Rob H Stigter, Kitty WM Bloemenkamp, Claudia A van Meir, Joris AM van der Post, Dick J Bekedam, Lucy SM Ribbert, Addie P Drogtrop, Paulien CM van der Salm, Anjoke JM Huisjes, Christine Willekes, Frans JME Roumen, Hubertina CJ Scheepers, Karin de Boer, Johannes J Duvekot, Jim G Thornton, Sicco A Scherjon
BMC Pregnancy and Childbirth , 2007, DOI: 10.1186/1471-2393-7-12
Abstract: The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm.This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term.Dutch Trial Register and ISRCTN-Register: ISRCTN10363217.Around 80% of intrauterine growth restricted (IUGR) infants are born at term [1]. When pregnancy is complicated by IUGR, there is, whether term or preterm, a clear association with an increase in neonatal mortality and neonatal morbidity (short and long term) [2-4]. The long term morbidity ranges from behavioral problems and minor developmental delay to spastic cerebral palsy [5-10]. However, not all studies, especially after excluding congenital anomalies, confirm these findings [11]. Besides fetal asphyxia, meconium aspiration, fetal heart rate abnormalities and low Apgar score, also more admittances to and longer stays at neonatal
Learning optimization models in the presence of unknown relations
Sicco Verwer,Yingqian Zhang,Qing Chuan Ye
Computer Science , 2014, DOI: 10.1016/j.artint.2015.05.004
Abstract: In a sequential auction with multiple bidding agents, it is highly challenging to determine the ordering of the items to sell in order to maximize the revenue due to the fact that the autonomy and private information of the agents heavily influence the outcome of the auction. The main contribution of this paper is two-fold. First, we demonstrate how to apply machine learning techniques to solve the optimal ordering problem in sequential auctions. We learn regression models from historical auctions, which are subsequently used to predict the expected value of orderings for new auctions. Given the learned models, we propose two types of optimization methods: a black-box best-first search approach, and a novel white-box approach that maps learned models to integer linear programs (ILP) which can then be solved by any ILP-solver. Although the studied auction design problem is hard, our proposed optimization methods obtain good orderings with high revenues. Our second main contribution is the insight that the internal structure of regression models can be efficiently evaluated inside an ILP solver for optimization purposes. To this end, we provide efficient encodings of regression trees and linear regression models as ILP constraints. This new way of using learned models for optimization is promising. As the experimental results show, it significantly outperforms the black-box best-first search in nearly all settings.
Gastrointestinal Stromal Tumor in Pregnancy: A Case Report
S. Scherjon,W. F. Lam,H. Gelderblom,F. W. Jansen
Case Reports in Medicine , 2009, DOI: 10.1155/2009/456402
Abstract: Background. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract and are diagnosed relatively seldom in pregnancy. Case. We describe a remarkable clinical course and long-term outcome, now nine years after first diagnosis, of a massive and metastatic, with a high malignancy grade GIST case, found in and treated from the first trimester of pregnancy onwards. Conclusion. GIST occurring during pregnancy is extremely rare. However, early diagnosis is important for optimal management. The recent better understanding of oncogenesis, the use of immunohistochemistry for differential diagnosis of GISTs, and the use of imatinib mesylate as the treatment of first choice are—as shown in this case—important for care of pregnant women with this type of malignancy.
Chronic Obstructive Pulmonary Disease Is Associated with Low Levels of Vitamin D
Louise Jeanette Pauline Persson, Marianne Aanerud, Pieter Sicco Hiemstra, Jon Andrew Hardie, Per Sigvald Bakke, Tomas Mikal Lind Eagan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038934
Abstract: Introduction COPD patients may be at increased risk for vitamin D (25(OH)D) deficiency, but risk factors for deficiency among COPD patients have not been extensively reported. Methods Serum 25(OH)D levels were measured by liquid chromatography double mass spectrometry in subjects aged 40–76 years from Western Norway, including 433 COPD patients (GOLD stage II-IV) and 325 controls. Levels <20 ng/mL defined deficiency. Season, sex, age, body mass index (BMI), smoking, GOLD stage, exacerbation frequency, arterial oxygen tension (PaO2), respiratory symptoms, depression (CES-D score≥16), comorbidities (Charlson score), treatment for osteoporosis, use of inhaled steroids, and total white blood count were examined for associations with 25(OH)D in both linear and logistic regression models. Results COPD patients had an increased risk for vitamin D deficiency compared to controls after adjustment for seasonality, age, smoking and BMI. Variables associated with lower 25(OH)D levels in COPD patients were obesity ( = ?6.63), current smoking ( = ?4.02), GOLD stage III- IV ( = ?4.71, = ?5.64), and depression ( = ?3.29). Summertime decreased the risk of vitamin D deficiency (OR = 0.22). Conclusion COPD was associated with an increased risk of vitamin D deficiency, and important disease characteristics were significantly related to 25(OH)D levels.
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