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- Dolberg Anderson, Ulrik, et al.
(author)
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Fetal hemoglobin and alpha(1)-microglobulin as first- and early second-trimester predictive biomarkers for preeclampsia
- 2011
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In: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 204:6
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of this study was to evaluate fetal hemoglobin (HbF) and alpha(1)-microglobulin (A1M) in maternal serum as first-trimester biomarkers for preeclampsia (PE). STUDY DESIGN: The design was a case-control study. We included 96 patients in the first trimester of pregnancy (60 with PE and 36 controls). Venous serum samples were analyzed for HbF and total hemoglobin (Hb) by enzyme-linked immunosorbent assay and for A1M by radioimmunoassay. Sensitivity and specificity was calculated by logistic regression and receiver operating characteristic curve analysis. RESULTS: The HbF/Hb ratio and A1M concentration were significantly elevated in serum from women with subsequent development of PE (P < .0001). The optimal sensitivity and specificity was obtained using the biomarkers in combination; 69% sensitivity for a 5% screen positive rate and 90% sensitivity for a 23% screen positive rate. CONCLUSION: The study suggests that HbF/Hb ratio in combination with A1M is predictive biomarkers for PE.
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| 2. |
- Gram, Magnus, et al.
(author)
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Increased levels of cell-free hemoglobin, oxidation markers, and the antioxidative heme scavenger alpha(1)-microglobulin in preeclampsia.
- 2010
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In: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849. ; 48, s. 284-291
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Journal article (peer-reviewed)abstract
- Preeclampsia is a major cause of morbidity and mortality during pregnancy. To date, the pathogenesis of the disease is not fully understood. Recent studies show that preeclampsia is associated with overexpression of the hemoglobin genes alpha2 and gamma and accumulation of the protein in the vascular lumen of the placenta. Hypothesizing that cell-free hemoglobin leaks from the placenta into the maternal circulation and contributes to the endothelial damage and symptoms by inducing oxidative stress, we analyzed fetal and adult hemoglobin (HbF, HbA), haptoglobin, oxidation markers, and the heme scavenger and antioxidant alpha(1)-microglobulin in plasma, urine, and placenta in preeclamptic women (n=28) and women with normal pregnancy (n=27). The mean plasma concentrations of HbF, HbA, protein carbonyl groups, membrane peroxidation capacity, and alpha(1)-microglobulin were significantly increased in preeclamptic women. The levels of total plasma Hb correlated strongly with the systolic blood pressure. The plasma haptoglobin concentrations of women with preeclampsia were significantly depressed. Increased amounts of alpha(1)-microglobulin mRNA and protein were found in placenta from preeclamptic women, and the levels of plasma and placenta alpha(1)-microglobulin correlated with the plasma Hb concentrations. The heme-degrading form t-alpha(1)-microglobulin was significantly increased in urine in preeclampsia. These results support the idea that hemoglobin-induced oxidative stress is a pathogenic factor in preeclampsia.
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| 6. |
- Centlow, Magnus, et al.
(author)
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Die in-vitro Perfusion der menschlichen Plazenta mit Eryhtrozyten und Xanthine Oxidase als in vitro Simulation von Praeeklampsie.
- 2009
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In: Zeitschrift für Geburtshilfe und Neonatologie. - : Georg Thieme Verlag KG. - 0948-2393 .- 1439-1651. ; 213:3, s. 89-95
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Preeclampsia is a major obstetric problem of unknown etiology. The fact that removal of the placenta is the only cure for preeclampsia, has led to the well-established hypothesis, that the placenta is central in the etiology. Gene profiling and proteomics studies have suggested oxidative stress caused by reperfusion and free oxygen radicals as a potential pathophysiological mechanism in preeclampsia. In this study, the dual placental perfusion model was used in order to evaluate the damaging effects of oxidative stress induced by xanthine/xanthine oxides and free hemoglobin.MATERIAL AND METHODS: The dual placenta perfusion model is a well-established in vitro model for functional placental studies. Placentas were perfused with medium containing either xanthine/xanthine oxidase or erythrocytes as a source of free hemoglobin. Concentration of free hemoglobin in the medium was measured by means of ELISA. Whole genome microarray technique and bioinformatics were used to evaluate the gene expression profile in the two groups.RESULTS: Substantial levels of free adult hemoglobin were detected in the perfusions. A total of 58 genes showed altered gene expression, the most altered were hemoglobin alpha, beta and gamma, tissue factor pathway inhibitor 2 and superoxide dismutase 2. Bioinformatics revealed that biological processes related to oxidative stress, anti-apoptosis and iron ion binding were significantly altered.CONCLUSIONS: The results suggest that perfusion with xanthine/xanthine oxidase and free hemoglobin induce changes in gene expression similar to what has been described for the preeclamptic placenta.
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| 7. |
- Centlow, Magnus, et al.
(author)
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Differential gene expression analysis of placentas with increased vascular resistance and pre-eclampsia using whole-genome microarrays.
- 2011
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In: Journal of Pregnancy. - : Hindawi Limited. - 2090-2727 .- 2090-2735. ; 2011:Mar 8
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Journal article (peer-reviewed)abstract
- Pre-eclampsia is a pregnancy complication characterized by hypertension and proteinuria. There are several factors associated with an increased risk of developing pre-eclampsia, one of which is increased uterine artery resistance, referred to as "notching". However, some women do not progress into pre-eclampsia whereas others may have a higher risk of doing so. The placenta, central in pre-eclampsia pathology, may express genes associated with either protection or progression into pre-eclampsia. In order to search for genes associated with protection or progression, whole-genome profiling was performed. Placental tissue from 15 controls, 10 pre-eclamptic, 5 pre-eclampsia with notching, and 5 with notching only were analyzed using microarray and antibody microarrays to study some of the same gene product and functionally related ones. The microarray showed 148 genes to be significantly altered between the four groups. In the preeclamptic group compared to notch only, there was increased expression of genes related to chemotaxis and the NF-kappa B pathway and decreased expression of genes related to antigen processing and presentation, such as human leukocyte antigen B. Our results indicate that progression of pre-eclampsia from notching may involve the development of inflammation. Increased expression of antigen-presenting genes, as seen in the notch-only placenta, may prevent this inflammatory response and, thereby, protect the patient from developing pre-eclampsia.
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| 8. |
- Centlow, Magnus, et al.
(author)
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Differential proteome analysis of the preeclamptic placenta using optimized protein extraction.
- 2010
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In: Journal of Biomedicine and Biotechnology. - : Hindawi Limited. - 1110-7251 .- 1110-7243. ; 2010:Sep 13
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Journal article (peer-reviewed)abstract
- The human placenta is a difficult tissue to work with using proteomic technology since it contains large amounts of lipids and glycogen. Both lipids and glycogen are known to interfere with the first step in the two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), the isoelectric focusing. In order to gain the best possible protein separation on 2D-PAGE, an optimized sample preparation protocol for placental proteins was developed. Two different buffers, urea/CHAPS and Hepes, were used for solubilization in combination with six different precipitation methods. The removal of glycogen from the samples by centrifugation was crucial for the final proteome maps. Solubilization with urea/CHAPS in combination with dichloromethane/methanol or acidified acetone proved to be the best precipitation procedures. When applied to clinical placenta samples apolipoprotein A1 was found to be accumulated in the preeclamptic placenta, where it may either have a nutritional effect or act as a modifier of signal transduction.
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| 10. |
- Centlow, Magnus
(author)
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Gene and Protein Profiling of the Preeclamptic Placenta
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Aims State-of-the-art methodology was used to screen and profile the placenta, gene and protein expression, for changes related to preeclampsia (PE) and cases with increased resistance in the uterine arteries. Women with increased resistance in the uterine arteries have increased risk of developing PE. Since not all of them develop PE, this group, identified by Doppler ultrasound, was included to search for genes and/or proteins that may protect them from developing PE. Results The PE placenta showed increased gene expression of fetal hemoglobin (Hb). Protein expression analysis confirmed the accumulation of free Hb, particularly the gamma chain was detected in the vascular lumen. Patients with increased resistance in the uterine arteries, expressed as a notch in blood velocity tracings recorded with Doppler ultrasound. Notching without PE, showed increased expression of genes related to apoptosis and antigen presentation in their placentas. In the notch placentas that later developed PE, an increased expression of genes related to inflammatory cell movement was seen. Antibody microarray screening of maternal plasma showed that late and early onset PE as well as PE with notching and IUGR showed different inflammatory responses. Conclusions The changes in gene expression suggested that PE may be a three-stage disease with notch as a reversible middle stage. Accumulation of inflammatory cells in the notch placenta may cause inflammation that drives the pathophysiology into PE. Increased expression of antigen presenting genes may protect the notch placenta from pro-inflammatory damage thereby preventing progression into PE. Free fetal Hb was identified as a possible placental factor that further induces inflammation and tissue damage. Increased maternal plasma levels of free fetal Hb may be used as a prognostic and diagnostic marker for PE. The maternal immune reaction and inflammatory response may be important factors that further determine the severity and the clinical manifestations of PE.
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