46 results on '"Russcher, H."'
Search Results
2. Angiogenic imbalance in pre‐eclampsia and fetal growth restriction: enhanced soluble fms‐like tyrosine kinase‐1 binding or diminished production of placental growth factor?
- Author
-
Kluivers, A. C. M., primary, Biesbroek, A., additional, Visser, W., additional, Saleh, L., additional, Russcher, H., additional, Danser, A. H. J., additional, and Neuman, R. I., additional
- Published
- 2023
- Full Text
- View/download PDF
3. Early pregnancy maternal and fetal angiogenic factors and fetal and childhood growth: the Generation R Study
- Author
-
Bergen, N.E., Bouwland-Both, M.I., Steegers-Theunissen, R.P.M., Hofman, A., Russcher, H., Lindemans, J., Jaddoe, V.W.V., and Steegers, E.A.P.
- Published
- 2015
- Full Text
- View/download PDF
4. Method comparison of three serum free light chain assays on the Roche Cobas 6000 c501 chemistry analyzer
- Author
-
Augustijn, Dieuwertje, Jacobs, J.F.M., Russcher, H., Augustijn, Dieuwertje, Jacobs, J.F.M., and Russcher, H.
- Abstract
Item does not contain fulltext
- Published
- 2021
5. Mass Spectrometry for Identification, Monitoring, and Minimal Residual Disease Detection of M-Proteins
- Author
-
Zajec, M., Langerhorst, P., VanDuijn, M.M., Gloerich, J., Russcher, H., Gool, A.J. van, Luider, T.M., Joosten, I., Rijke, Y.B. de, Jacobs, J.F.M., Zajec, M., Langerhorst, P., VanDuijn, M.M., Gloerich, J., Russcher, H., Gool, A.J. van, Luider, T.M., Joosten, I., Rijke, Y.B. de, and Jacobs, J.F.M.
- Abstract
Contains fulltext : 218890.pdf (publisher's version ) (Open Access)
- Published
- 2020
6. A novel haemocytometric covid-19 prognostic score developed and validated in an observational multicentre european hospital-based study
- Author
-
Linssen, J. (Joachim), Ermens, A. (Anthony), Berrevoets, M. (Marvin), Seghezzi, M. (Michela), Previtali, G. (Giulia), Brugge, S.S. (Simone van der Sar-van der), Russcher, H. (Henk), Verbon, A. (Annelies), Gillis, J. (Judith), Riedl, J.A. (Jurgen), Jongh, E. (Eva de), Saker, J. (Jarob), Münster, M. (Marion), Munnix, I.C.A. (Imke CA), Dofferhoff, A.S.M. (Anton), Scharnhorst, V., Ammerlaan, H.S.M. (Heidi), Deiteren, K. (Kathleen), Bakker, S.J.L. (Stephan JL), van Pelt, L.J. (Lucas Joost), Hingh, Y.K. (Yvette Kluiters-De), Leers, J. (Joerg), Ven, A.D. (Andre´) van, Linssen, J. (Joachim), Ermens, A. (Anthony), Berrevoets, M. (Marvin), Seghezzi, M. (Michela), Previtali, G. (Giulia), Brugge, S.S. (Simone van der Sar-van der), Russcher, H. (Henk), Verbon, A. (Annelies), Gillis, J. (Judith), Riedl, J.A. (Jurgen), Jongh, E. (Eva de), Saker, J. (Jarob), Münster, M. (Marion), Munnix, I.C.A. (Imke CA), Dofferhoff, A.S.M. (Anton), Scharnhorst, V., Ammerlaan, H.S.M. (Heidi), Deiteren, K. (Kathleen), Bakker, S.J.L. (Stephan JL), van Pelt, L.J. (Lucas Joost), Hingh, Y.K. (Yvette Kluiters-De), Leers, J. (Joerg), and Ven, A.D. (Andre´) van
- Abstract
COVID-19 induces haemocytometric changes. Complete blood count changes, including new cell activation parameters, from 982 confirmed COVID-19 adult patients from 11 European hospitals were retrospectively analysed for distinctive patterns based on age, gender, clinical severity, symptom duration and hospital days. The observed haemocytometric patterns formed the basis to develop a multi-haemocytometric-parameter prognostic score to predict, during the first three days after presentation, which patients will recover without ventilation or deteriorate within a two-week timeframe, needing intensive care or with fatal outcome. The prognostic score, with ROC curve AUC at baseline of 0.753 (95% CI 0.723-0.781) increasing to 0.875 (95% CI 0.806-0.926) on day 3, was superior to any individual parameter at distinguishing between clinical severity. Findings were confirmed in a validation cohort. Aim is that the score and haemocytometry results are simultaneously provided by analyser software, enabling wide applicability of the score as haemocytometry is commonly requested in COVID-19 patients.
- Published
- 2020
- Full Text
- View/download PDF
7. Massive hemolysis due to Clostridium perfringens: a laboratory's perspective
- Author
-
Smit, B. (Bob), Van Der Helm, M.W. (Marinke W.), Bosma, M. (Madeleen), Hudig, F. (Francisca), Russcher, H. (Henk), Smit, B. (Bob), Van Der Helm, M.W. (Marinke W.), Bosma, M. (Madeleen), Hudig, F. (Francisca), and Russcher, H. (Henk)
- Published
- 2020
- Full Text
- View/download PDF
8. A summary of the diagnostic and prognostic value of hemocytometry markers in COVID-19 patients
- Author
-
Khartabil, T.A.T. (T A Tania), Russcher, H. (Henk), van der Ven, A.A. (Ajam Andre), Rijke, Y.B. (Yolanda) de, Khartabil, T.A.T. (T A Tania), Russcher, H. (Henk), van der Ven, A.A. (Ajam Andre), and Rijke, Y.B. (Yolanda) de
- Abstract
Many studies have reported hemocytometric changes in COVID-19 infection at admission and during the course of disease, but an overview is lacking. We provide a summary of the literature of hemocytometric changes and evaluate whether these changes may assist clinicians in diagnosing and predicting disease progression of COVID-19. Eighty-three out of 250 articles from December 2019 to 20 May 2020 were included from the databases, PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv. Our review of the literature indicates that lymphopenia and an elevated neutrophil/lymphocyte ratio are the most consistent abnormal hemocytometric findings and that these alterations may augment in the course of time, especially in those with severe disease.
- Published
- 2020
- Full Text
- View/download PDF
9. Mass Spectrometry for Identification, Monitoring, and Minimal Residual Disease Detection of M-Proteins
- Author
-
Zajec, M. (Marina), Langerhorst, P. (P.), Duijn, M.M. (Martijn) van, Gloerich, J. (Jolein), Russcher, H. (Henk), van Gool, A.J. (A. J.), Luider, T.M. (Theo), Joosten, I. (Irma), Rijke, Y.B. (Yolanda) de, Jacobs, J.F.M. (Joannes F. M.), Zajec, M. (Marina), Langerhorst, P. (P.), Duijn, M.M. (Martijn) van, Gloerich, J. (Jolein), Russcher, H. (Henk), van Gool, A.J. (A. J.), Luider, T.M. (Theo), Joosten, I. (Irma), Rijke, Y.B. (Yolanda) de, and Jacobs, J.F.M. (Joannes F. M.)
- Abstract
BACKGROUND: Monoclonal gammopathies (MGs) are plasma cell disorders defined by the clonal expansion of plasma cells, resulting in the characteristic excretion of a monoclonal immunoglobulin (M-protein). M-protein detection and quantification are integral parts of the diagnosis
- Published
- 2020
- Full Text
- View/download PDF
10. Mass Spectrometry for Identification, Monitoring, and Minimal Residual Disease Detection of M-Proteins
- Author
-
Zajec, M, primary, Langerhorst, P, primary, VanDuijn, M M, primary, Gloerich, J, primary, Russcher, H, primary, van Gool, A J, primary, Luider, T M, primary, Joosten, I, primary, de Rijke, Y B, primary, and Jacobs, J F M, primary
- Published
- 2020
- Full Text
- View/download PDF
11. Method comparison of four clinically available assays for serum free light chain analysis
- Author
-
Fleming, C.K.A., Swarttouw, T., Kat Angelino, C.M. de, Jacobs, J.F.M., Russcher, H., Fleming, C.K.A., Swarttouw, T., Kat Angelino, C.M. de, Jacobs, J.F.M., and Russcher, H.
- Abstract
Item does not contain fulltext
- Published
- 2019
12. Vox Sanguinis International Forum on the use of prehospital blood products and pharmaceuticals in the treatment of patients with traumatic hemorrhage
- Author
-
Yazer, M. H., Spinella, P. C., Allard, S., Roxby, D., So-Osman, C., Lozano, M., Gunn, K., Shih, A. W., Stensballe, J., Johansson, P. I., Hansen, M. Bagge, Maegele, M., Doughty, H., Crombie, N., Jenkins, D. H., McGinity, A. C., Schaefer, R. M., Martinaud, C., Shinar, E., Strugo, R., Chen, J., Russcher, H., Yazer, M. H., Spinella, P. C., Allard, S., Roxby, D., So-Osman, C., Lozano, M., Gunn, K., Shih, A. W., Stensballe, J., Johansson, P. I., Hansen, M. Bagge, Maegele, M., Doughty, H., Crombie, N., Jenkins, D. H., McGinity, A. C., Schaefer, R. M., Martinaud, C., Shinar, E., Strugo, R., Chen, J., and Russcher, H.
- Published
- 2018
13. Soluble fms-like tyrosine kinase-1 and placental growth factor kinetics during and after pregnancy in women with suspected or confirmed pre-eclampsia
- Author
-
Saleh, L., primary, van den Meiracker, A. H., additional, Geensen, R., additional, Kaya, A., additional, Roeters van Lennep, J. E., additional, Duvekot, J. J., additional, Verdonk, K., additional, Steegers, E. A. P., additional, Russcher, H., additional, Danser, A. H. J., additional, and Visser, W., additional
- Published
- 2018
- Full Text
- View/download PDF
14. Chronic air pollution exposure during pregnancy and maternal and fetal c-reactive protein levels: The generation R study
- Author
-
Hooven, E.H. van den, Kluizenaar, Y. de, Pierik, F.H., Hofman, A., Ratingen, S.W. van, Zandveld, P.Y.J., Lindemans, J., Russcher, H., Steegers, E.A.P., Miedema, H.M.E., and Jaddoe, V.W.V.
- Subjects
Inflammation ,Earth & Environment ,Air pollution ,Dispersion modeling ,C-reactive protein ,Urban Development ,Health ,Pregnancy ,UES - Urban Environment & Safety ,Built Environment ,EELS - Earth, Environmental and Life Sciences ,Particulate matter ,Nitrogen dioxide - Abstract
Background: Exposure to air pollution has been associated with higher C-reactive protein (CRP) levels, suggesting an inflammatory response. Not much is known about this association in pregnancy. Objectives: We investigated the associations of air pollution exposure during pregnancy with maternal and fetal CRP levels in a population-based cohort study in the Netherlands. Methods: Particulate matter (PM) with an aerodynamic diameter ≤ 10 μm (PM10) and nitrogen dioxide (NO 2) levels were estimated at the home address using dispersion modeling for different averaging periods preceding the blood sampling (1 week, 2 weeks, 4 weeks, and total pregnancy). High-sensitivity CRP levels were measured in maternal blood samples in early pregnancy (n = 5,067) and in fetal cord blood samples at birth (n = 4,450). Results: Compared with the lowest quartile, higher PM10 exposure levels for the prior 1 and 2 weeks were associated with elevated maternal CRP levels (> 8 mg/L) in the first trimester [fourth PM10 quartile for the prior week: odds ratio (OR), 1.32; 95% confidence interval (CI): 1.08, 1.61; third PM10 quartile for the prior 2 weeks: OR, 1.28; 95% CI: 1.06, 1.56]; however, no clear dose-response relationships were observed. PM10 and NO2 exposure levels for 1, 2, and 4 weeks preceding delivery were not consistently associated with fetal CRP levels at delivery. Higher long-term PM10 and NO 2 exposure levels (total pregnancy) were associated with elevated fetal CRP levels (> 1 mg/L) at delivery (fourth quartile PM10: OR, 2.18; 95% CI: 1.08, 4.38; fourth quartile NO 2: OR, 3.42; 95% CI: 1.36, 8.58; p-values for trend < 0.05). Conclusions: Our results suggest that exposure to air pollution during pregnancy may lead to maternal and fetal inflammatory responses.
- Published
- 2012
15. Air Pollution Exposure and Markers of Placental Growth and Function: The Generation R Study
- Author
-
Hooven, E.H. van den, Pierik, F.H., Kluizenaar, Y. de, Hofman, A., Ratingen, S.W. van, Zandveld, P.Y.J., Russcher, H., Lindemans, J., Miedema, H.M.E., Steegers, E.A.P., and Jaddoe, V.W.V.
- Subjects
Health ,Earth & Environment ,UES - Urban Environment & Safety ,Healthy for Life ,EELS - Earth, Environmental and Life Sciences ,Healthy Living - Published
- 2012
16. Maternal soluble fms-like tyrosine kinase-1, placental growth factor, plasminogen activator inhibitor-2, and folate concentrations and early fetal size: the Generation R study
- Author
-
Bouwland-Both, M.I., Steegers, E.A.P., Lindemans, J., Russcher, H., Hofman, A., Geurts-Moespot, A.J., Sweep, C.G.J., Jaddoe, V.W., Steegers-Theunissen, R.P.M., Bouwland-Both, M.I., Steegers, E.A.P., Lindemans, J., Russcher, H., Hofman, A., Geurts-Moespot, A.J., Sweep, C.G.J., Jaddoe, V.W., and Steegers-Theunissen, R.P.M.
- Abstract
Item does not contain fulltext, OBJECTIVE: Fetal growth is dependent on adequate development of the placenta. Impaired angiogenesis and vasculogenesis in early pregnancy compromises placental and embryonic development. The proteins soluble fms-like tyrosine kinase (sFlt)-1, placental growth factor (PlGF), and plasminogen activator inhibitor (PAI)-2, and the B vitamin folate are determinants of placental development. This study aims to identify associations between these maternal biomarkers and early fetal size. STUDY DESIGN: From a prospective birth cohort study in The Netherlands, 1491 pregnant women were selected for this study. At a mean gestational age (GA) of 12.4 weeks (SD 0.8) maternal venous blood samples were obtained to determine the concentrations of sFlt-1, PlGF, PAI-2, and folate. Early fetal size was assessed with measurement of the crown-to-rump length (CRL) at a mean of 12.4 weeks' GA (SD 0.8). Analyses were performed using multivariable linear regression analyses with the biomarkers (continuous, quintiles) as regressors and CRL as main outcome measure. RESULTS: Linear trend analysis showed positive associations between maternal sFlt-1 (P < .001), PlGF (P = .042), PAI-2 (P < .001), and folate (P = .039) and CRL. These associations were independent of GA, maternal age, height, body mass index, ethnicity, fetal sex, parity, educational level, smoking, and folic acid supplement use (folate not adjusted). CONCLUSION: sFlt-1, PlGF, PAI-2, and folate are positively associated with first-trimester fetal size.
- Published
- 2013
17. Angiogenic and fibrinolytic factors in blood during the first half of pregnancy and adverse pregnancy outcomes
- Author
-
Coolman, M. (Marianne), Timmermans, S. (Sarah), Groot, C.J.M. (Christianne) de, Russcher, H. (Henk), Lindemans, J. (Jan), Hofman, A. (Albert), Geurts-Moespot, A. (Anneke), Sweep, F.C. (Fred), Jaddoe, V.W.V. (Vincent), Steegers, E.A.P. (Eric), Coolman, M. (Marianne), Timmermans, S. (Sarah), Groot, C.J.M. (Christianne) de, Russcher, H. (Henk), Lindemans, J. (Jan), Hofman, A. (Albert), Geurts-Moespot, A. (Anneke), Sweep, F.C. (Fred), Jaddoe, V.W.V. (Vincent), and Steegers, E.A.P. (Eric)
- Abstract
Objective: To estimate whether the imbalance of angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor) and fibrinolytic factors (plasminogen activator inhibitor-2 [PAI-2]) might affect placentation in early pregnancy. Methods: We studied the associations of maternal soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 concentrations in the first trimester (before 18 weeks of gestation) and soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in the second trimester (18-25 weeks of gestation) with placental function and adverse pregnancy outcomes. This study was embedded in a population-based prospective cohort study. Data were used from 7,519 women. Biomarker concentrations were divided into deciles and evaluated in multivariable linear and logistic regression models. Results: First-trimester high soluble fms-like tyrosine kinase-1 was associated with a 5.2% lower uterine artery index in the second-trimester and a 1.6% higher birth weight (55 g, confidence interval [CI] 15-95). Neither in the first nor in the second trimester were soluble fms-like tyrosine kinase-1 concentrations significantly associated with preeclampsia. First-trimester low placental growth factor was associated with a 6.1% higher uterine artery index and a 3.4% lower birth weight (-115 g, CI-157 to-74). First-trimester low placental growth factor was associated with fetal growth restriction (odds ratio [OR] 2.62, CI 1.68-4.08) and preeclampsia (OR 2.46, CI 1.49-4.08). First-trimester low PAI-2 was associated with a 1.9% higher uterine artery index and a 2.7% lower birth weight (-94 g, CI-136 to-51). First-trimester low PAI-2 was associated with a higher risk of fetal growth restriction (OR 2.22, CI 1.39-3.55). Conclusion: First-half-of-pregnancy concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 are associated with uteroplacental vascular resistance, placental weight, and birth weight. Moreo
- Published
- 2012
- Full Text
- View/download PDF
18. Air pollution exposure and markers of placental growth and function: The Generation R Study
- Author
-
Hooven, E.H. (Edith) van den, Pierik, F.H. (Frank), Kluizenaar, Y. (Yvonne) de, Hofman, A. (Albert), Ratingen, S.W. (Sjoerd) van, Zandveld, P.Y.J. (Peter), Russcher, H. (Henk), Lindemans, J. (Jan), Miedema, H.M. (Henk), Steegers, E.A.P. (Eric), Jaddoe, V.W.V. (Vincent), Hooven, E.H. (Edith) van den, Pierik, F.H. (Frank), Kluizenaar, Y. (Yvonne) de, Hofman, A. (Albert), Ratingen, S.W. (Sjoerd) van, Zandveld, P.Y.J. (Peter), Russcher, H. (Henk), Lindemans, J. (Jan), Miedema, H.M. (Henk), Steegers, E.A.P. (Eric), and Jaddoe, V.W.V. (Vincent)
- Abstract
Background: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications. Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands. Methods: We estimated levels of particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second-trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. Results: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-µg/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (–11.8 g; 95% CI: –20.9, –2.7, and –10.7 g; 95% CI: –19.0, –2.4, respectively, per 10-µg/m3 increase in the prior 2 months), but not with placenta to birth weight ratio. Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal
- Published
- 2012
- Full Text
- View/download PDF
19. Angiogenic and fibrinolytic factors in blood during the first half of pregnancy and adverse pregnancy outcomes.
- Author
-
Coolman, M., Timmermans, S., Groot, C.J. de, Russcher, H., Lindemans, J., Hofman, A., Geurts-Moespot, A., Sweep, C.G.J., Jaddoe, V.V., Steegers, E.A.P., Coolman, M., Timmermans, S., Groot, C.J. de, Russcher, H., Lindemans, J., Hofman, A., Geurts-Moespot, A., Sweep, C.G.J., Jaddoe, V.V., and Steegers, E.A.P.
- Abstract
01 juni 2012, Item does not contain fulltext, OBJECTIVE: To estimate whether the imbalance of angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor) and fibrinolytic factors (plasminogen activator inhibitor-2 [PAI-2]) might affect placentation in early pregnancy. METHODS: We studied the associations of maternal soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 concentrations in the first trimester (before 18 weeks of gestation) and soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in the second trimester (18-25 weeks of gestation) with placental function and adverse pregnancy outcomes. This study was embedded in a population-based prospective cohort study. Data were used from 7,519 women. Biomarker concentrations were divided into deciles and evaluated in multivariable linear and logistic regression models. RESULTS: First-trimester high soluble fms-like tyrosine kinase-1 was associated with a 5.2% lower uterine artery index in the second-trimester and a 1.6% higher birth weight (55 g, confidence interval [CI] 15-95). Neither in the first nor in the second trimester were soluble fms-like tyrosine kinase-1 concentrations significantly associated with preeclampsia. First-trimester low placental growth factor was associated with a 6.1% higher uterine artery index and a 3.4% lower birth weight (-115 g, CI -157 to -74). First-trimester low placental growth factor was associated with fetal growth restriction (odds ratio [OR] 2.62, CI 1.68-4.08) and preeclampsia (OR 2.46, CI 1.49-4.08). First-trimester low PAI-2 was associated with a 1.9% higher uterine artery index and a 2.7% lower birth weight (-94 g, CI -136 to -51). First-trimester low PAI-2 was associated with a higher risk of fetal growth restriction (OR 2.22, CI 1.39-3.55). CONCLUSION: First-half-of-pregnancy concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 are associated with uteroplacental vascular resistance, placental weight, and birth weight. M
- Published
- 2012
20. Klinische chemie voor iedereen: het Wikipedia-project
- Author
-
Russcher, H. (Henk), Herwaarden, A.E. (Antonius) van, Boesten, L.S.M. (Lianne S.M.), Kemna, E.H.J.M., Curvers, J., Heijboer, M.P. (Rien), Engbers-Buijtenhuijs, P., Deckers, M.M.L., Russcher, H. (Henk), Herwaarden, A.E. (Antonius) van, Boesten, L.S.M. (Lianne S.M.), Kemna, E.H.J.M., Curvers, J., Heijboer, M.P. (Rien), Engbers-Buijtenhuijs, P., and Deckers, M.M.L.
- Abstract
Public relations (PR) and information to patients are key goals of the Dutch Society of Clinical Chemistry (NVKC). In this paper several initiatives will be discussed that have been undertaken to meet this statement. The Wikipedia project is one of those initiatives in which information concerning clinical chemistry is added or revised to the Dutch version of the online encyclopaedia Wikipedia. Over 100 tests and items of clinical chemistry have been added or revised and are recognized as a separate category within this online encyclopaedia. Statistical analysis showed an increase in the number of visitors to these articles of Wikipedia. Furthermore, by adding and improving the available information, the quality of the information provided online is enhanced. In conclusion: the attribution of health care professionals to this public domain leads to enhanced access of high quality information for the main public to clinical chemistry in general and to specific laboratory blood tests.
- Published
- 2010
21. Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol
- Author
-
Russcher, H. (Henk) and Russcher, H. (Henk)
- Abstract
Synthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this moment is to develop insights into the cause of the differences in the response between individuals to therapeutically applied GCs. Some patients respond to low doses, with or without side effects, while others do not respond at all. This thesis discusses a number of possible explanations for these differences in GC sensitivity and is focused on genetic, but also on transcriptional and translational aspects of the GR gene. Furthermore, it is also described how glucocorticoid sensitivity disorders can be characterized clinically and biochemically. An important tool in these studies has been a newly developed bioassay, measuring cellular GC sensitivity ex vivo, based on GR action at the transcriptional level by studying GC-regulated mRNA expression (chapter 2). Various polymorphism in the GR gene (N363S, ER22/23EK, and 9beta) are shown to affect GC sensitivity in vivo and in/ex vitro and result in a wide variety of phenotypic signs (chapters 3, 4, and 5). Furthermore, studies described in chapter 4, 5, 6, and 7 have demonstrated that also transcriptional and translational variants of the GR and the use of different promoters could modulate GC sensitivity. These factors modulating inter- individual sensitivity to GCs may have consequences for the use of GCs in a clinical setting. When treating patients with GCs, they need an individually determined optimal dose to obtain a balance between beneficial and adverse effects.
- Published
- 2006
22. Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2.
- Author
-
Smit, P. (Pauline), Russcher, H. (Henk), Jong, F.H. (Frank) de, Brinkmann, A.O. (Albert), Lamberts, S.W.J. (Steven), Koper, J.W. (Jan), Smit, P. (Pauline), Russcher, H. (Henk), Jong, F.H. (Frank) de, Brinkmann, A.O. (Albert), Lamberts, S.W.J. (Steven), and Koper, J.W. (Jan)
- Abstract
Individual glucocorticoid (GC) sensitivity was determined by measuring the effects of several clinically used GCs on transactivation of the GC-induced leucine zipper (GILZ) gene and on transrepression of the IL-2 gene using quantitative real-time PCR. A clear difference in relative potencies for transactivation and transrepression of the various GCs was observed, suggesting differential effects. To determine whether the in vitro outcomes could predict in vivo effects of GCs, 15 individuals underwent a 0.25-mg dexamethasone (DEX) suppression test (DST) while determining GILZ and IL-2 mRNA levels in their peripheral blood mononuclear cells incubated with hydrocortisone, DEX, budesonide, and prednisolone. No correlations were found between the DST and the two expression assays. However, significant correlations existed between hydrocortisone and DEX (r = 0.52; P = 0.046), hydrocortisone and budesonide (r = 0.48; P = 0.069), and hydrocortisone and prednisolone (r = 0.86; P = 0.007) regarding GILZ mRNA levels, and between hydrocortisone and DEX (r = 0.62; P = 0.014), hydrocortisone and budesonide (r = 0.71; P = 0.003), and hydrocortisone and prednisolone (r = 0.71; P = 0.047) regarding IL-2 mRNA levels. In conclusion, intra- and inter-individual variations in GC sensitivity were observed using two expression assays representing GC-mediated transactivation and transrepression. The two expression assays did not correlate with each other or with the results of the DST. This suggests that regulation of the hypothalamic-pituitary-adrenal axis is more complex. However, within an individual person, these two tests combined might predict what type and dosage of GC will be preferable in individual patients for its inhibitory clinical effects, together with relatively fewer transactivating effects related to adverse effects.
- Published
- 2005
- Full Text
- View/download PDF
23. Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.
- Author
-
Russcher, H. (Henk), Smit, P. (Pauline), Akker, E.L.T. (Erica) van den, Rossum, E.F.C. (Liesbeth) van, Brinkmann, A.O. (Albert), Jong, F.H. (Frank) de, Lamberts, S.W.J. (Steven), Koper, J.W. (Jan), Russcher, H. (Henk), Smit, P. (Pauline), Akker, E.L.T. (Erica) van den, Rossum, E.F.C. (Liesbeth) van, Brinkmann, A.O. (Albert), Jong, F.H. (Frank) de, Lamberts, S.W.J. (Steven), and Koper, J.W. (Jan)
- Abstract
CONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND DESIGN: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor kappaB-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR. RESULTS: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (-14 +/- 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: -48 +/- 6%, P < 0.01, n = 1; heterozygous: -21 +/- 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 +/- 3%; P < 0.02) and ex vivo (homozygous: 204 +/- 19%, P < 0.0001, n = 1; heterozygous: 124 +/- 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR. CONCLUSION: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.
- Published
- 2005
- Full Text
- View/download PDF
24. Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism.
- Author
-
Russcher, H. (Henk), Rossum, E.F.C. (Liesbeth) van, Jong, F.H. (Frank) de, Brinkmann, A.O. (Albert), Lamberts, S.W.J. (Steven), Koper, J.W. (Jan), Russcher, H. (Henk), Rossum, E.F.C. (Liesbeth) van, Jong, F.H. (Frank) de, Brinkmann, A.O. (Albert), Lamberts, S.W.J. (Steven), and Koper, J.W. (Jan)
- Abstract
One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not af
- Published
- 2005
- Full Text
- View/download PDF
25. Differential diagnosis of preeclampsia: remember the soluble fms-like tyrosine kinase 1/placental growth factor ratio.
- Author
-
Verdonk K, Visser W, Russcher H, Danser AH, Steegers EA, van den Meiracker AH, Verdonk, Koen, Visser, Willy, Russcher, Henk, Danser, A H Jan, Steegers, Eric A P, and van den Meiracker, Anton H
- Published
- 2012
- Full Text
- View/download PDF
26. Retrospective Longitudinal Monitoring of Multiple Myeloma Patients by Mass Spectrometry Using Archived Serum Protein Electrophoresis Gels and De Novo Sequence Analysis.
- Author
-
Noori S, Zajec M, Russcher H, Tintu AN, Broijl A, Jacobs JFM, Luider TM, de Rijke YB, and vanDuijn MM
- Published
- 2022
- Full Text
- View/download PDF
27. Omeprazole Administration in Preterm Preeclampsia: a Randomized Controlled Trial to Study Its Effect on sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1), PlGF (Placental Growth Factor), and ET-1 (Endothelin-1).
- Author
-
Neuman RI, Baars MD, Saleh L, Broekhuizen M, Nieboer D, Cornette J, Schoenmakers S, Verhoeven M, Koch BCP, Russcher H, van den Berg SAA, van den Meiracker AH, Visser W, and Danser AHJ
- Subjects
- Adult, Biomarkers metabolism, Endothelin-1 metabolism, Esomeprazole, Female, Humans, Infant, Infant, Newborn, Omeprazole metabolism, Omeprazole pharmacology, Placenta metabolism, Placenta Growth Factor metabolism, Pregnancy, Proton Pump Inhibitors, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism, Pre-Eclampsia diagnosis, Pre-Eclampsia drug therapy, Pre-Eclampsia metabolism
- Abstract
Background: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors., Methods: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole., Results: Mean maternal age was 30 years, and median gestational age was 30
+3 weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P =0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio's 0.43-0.59), while only esomeprazole inhibited placental sFlt-1 release., Conclusions: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.- Published
- 2022
- Full Text
- View/download PDF
28. Fast detection and quantification of Plasmodium species infected erythrocytes in a non-endemic region by using the Sysmex XN-31 analyzer.
- Author
-
Khartabil TA, de Rijke YB, Koelewijn R, van Hellemond JJ, and Russcher H
- Subjects
- Erythrocytes, Humans, Parasitemia diagnosis, Plasmodium falciparum, Malaria diagnosis, Plasmodium
- Abstract
Background: Due to increased travel from endemic countries, malaria occurs more frequently in non-endemic regions. It is a challenge for diagnostic laboratories in non-endemic countries to provide reliable results, as experience of staff is often limited to only a few cases per year. This study evaluated the diagnostic accuracy of the fully automated Sysmex XN-31 malaria analyzer in a routine diagnostic setting in a non-endemic region was evaluated., Methods: Samples from 112 patients suspected for malaria were examined by the Sysmex XN-31 analyzer to determine the absolute count of malaria-infected red blood cells count (MI-RBC/µL). Microscopic examination of both Quantitative Buffy Coat capillary tubes and thick and thin blood films were used as reference methods. Limits of blank (LoB), detection (LoD) and quantification (LoQ) were investigated using an in vitro Plasmodium falciparum culture. Nine hundred twenty samples of patients with RBC abnormalities were included to determine which RBC abnormalities trigger indeterminate or false positive results., Results: No false positive nor false negative results were obtained for the examined patient samples suspected for malaria. For 3% of samples an indeterminate result by the XN-31 was obtained. The Passing-Bablok regression line for diagnostic accuracy of the parasitaemia was y = 39.75 + 0.7892 × showing a positive bias of about 21% when comparing the MI-RBC results to microscopy. The LoB, LoD and LoQ were calculated to be 4.7, 5.9, and 19.0 infected RBC/μL, respectively. From the 920 abnormal RBC samples collected, 4.6% resulted in a false positive MI-RBC result and almost half of the samples produced indeterminate results. These results were related to increases in nucleated red blood cells, reticulocytes and other abnormal RBC morphologies such as sickle cells., Conclusions: Based on the results, the XN-31 is a fast and reliable screening method in the detection and quantification of Plasmodium species in patients However, if an abnormal red blood cell morphology is present, the results of the XN-31 should be interpreted with caution as false positive results can be caused by interfering abnormal erythrocytes., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
29. Accurate Prediction of Total PlGF (Placental Growth Factor) From Free PlGF and sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1): Evidence for Markedly Elevated PlGF Levels in Women With Acute Fatty Liver of Pregnancy.
- Author
-
Neuman RI, Saleh L, Verdonk K, van den Meiracker AH, Russcher H, Metselaar HJ, Visser W, and Danser AHJ
- Subjects
- Adult, Biomarkers blood, Female, Humans, Pregnancy, Fatty Liver blood, Placenta Growth Factor blood, Pregnancy Complications blood, Vascular Endothelial Growth Factor Receptor-1 blood
- Abstract
[Figure: see text].
- Published
- 2021
- Full Text
- View/download PDF
30. COVID-19-associated pseudothrombocytopenia.
- Author
-
Van Dijck R, Lauw MN, Swinkels M, Russcher H, and Jansen AJG
- Abstract
Competing Interests: The authors declare that there is no conflict of interest.
- Published
- 2021
- Full Text
- View/download PDF
31. A novel haemocytometric COVID-19 prognostic score developed and validated in an observational multicentre European hospital-based study.
- Author
-
Linssen J, Ermens A, Berrevoets M, Seghezzi M, Previtali G, van der Sar-van der Brugge S, Russcher H, Verbon A, Gillis J, Riedl J, de Jongh E, Saker J, Münster M, Munnix IC, Dofferhof A, Scharnhorst V, Ammerlaan H, Deiteren K, Bakker SJ, Van Pelt LJ, Kluiters-de Hingh Y, Leers MP, and van der Ven AJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Blood Cell Count instrumentation, Blood Cell Count methods, COVID-19 epidemiology, COVID-19 virology, Cohort Studies, Europe, Female, Humans, Male, Middle Aged, Pandemics, Prognosis, Retrospective Studies, SARS-CoV-2 physiology, Young Adult, Blood Cell Count statistics & numerical data, COVID-19 blood, Hospitalization statistics & numerical data, Hospitals
- Abstract
COVID-19 induces haemocytometric changes. Complete blood count changes, including new cell activation parameters, from 982 confirmed COVID-19 adult patients from 11 European hospitals were retrospectively analysed for distinctive patterns based on age, gender, clinical severity, symptom duration, and hospital days. The observed haemocytometric patterns formed the basis to develop a multi-haemocytometric-parameter prognostic score to predict, during the first three days after presentation, which patients will recover without ventilation or deteriorate within a two-week timeframe, needing intensive care or with fatal outcome. The prognostic score, with ROC curve AUC at baseline of 0.753 (95% CI 0.723-0.781) increasing to 0.875 (95% CI 0.806-0.926) on day 3, was superior to any individual parameter at distinguishing between clinical severity. Findings were confirmed in a validation cohort. Aim is that the score and haemocytometry results are simultaneously provided by analyser software, enabling wide applicability of the score as haemocytometry is commonly requested in COVID-19 patients., Competing Interests: JL, JS, MM is a permanent employee of Sysmex Europe GMBH who provided free of charge study reagents to the study centres. AE, MB, MS, GP, Sv, HR, AV, JG, JR, Ed, IM, AD, VS, HA, KD, SB, LV, YK, ML No competing interests declared, Av has an ad hoc consultancy agreement with Sysmex Europe GMBH who provided free of charge study reagents to the study centres., (© 2020, Linssen et al.)
- Published
- 2020
- Full Text
- View/download PDF
32. Angiogenic Markers Predict Pregnancy Complications and Prolongation in Preeclampsia: Continuous Versus Cutoff Values.
- Author
-
Saleh L, Vergouwe Y, van den Meiracker AH, Verdonk K, Russcher H, Bremer HA, Versendaal HJ, Steegers EAP, Danser AHJ, and Visser W
- Subjects
- Adult, Female, Gestational Age, Humans, Middle Aged, Netherlands epidemiology, Predictive Value of Tests, Pregnancy, Prognosis, Reproducibility of Results, Risk Factors, Placenta Growth Factor blood, Pre-Eclampsia blood, Pre-Eclampsia diagnosis, Pre-Eclampsia epidemiology, Vascular Endothelial Growth Factor Receptor-1 blood
- Abstract
To assess the incremental value of a single determination of the serum levels of sFlt-1 (soluble Fms-like tyrosine kinase 1) and PlGF (placental growth factor) or their ratio, without using cutoff values, for the prediction of maternal and fetal/neonatal complications and pregnancy prolongation, 620 women with suspected/confirmed preeclampsia, aged 18 to 48 years, were included in a prospective, multicenter, observational cohort study. Women had singleton pregnancies and a median pregnancy duration of 34 (range, 20-41) weeks. Complications occurred in 118 women and 248 fetuses. The median duration between admission and delivery was 12 days. To predict prolongation, PlGF showed the highest incremental value ( R
2 =0.72) on top of traditional predictors (gestational age at inclusion, diastolic blood pressure, proteinuria, creatinine, uric acid, alanine transaminase, lactate dehydrogenase, and platelets) compared with R2 =0.53 for the traditional predictors only. sFlt-1 showed the highest value to discriminate women with and without maternal complications (C-index=0.83 versus 0.72 for the traditional predictors only), and the sFlt-1/PlGF ratio showed the highest value to discriminate fetal/neonatal complications (C-index=0.86 versus 0.78 for the traditional predictors only). Applying previously suggested cutoff values for the sFlt-1/PlGF ratio yielded lower incremental values than applying continuous values. In conclusion, sFlt-1 and PlGF are strong and independent predictors for days until delivery along with maternal and fetal/neonatal complications on top of the traditional criteria. Their use as continuous variables (instead of applying cutoff values for different gestational ages) should now be tested in a prospective manner, making use of an algorithm calculating the risk of an individual woman with suspected/confirmed preeclampsia to develop complications., (© 2017 American Heart Association, Inc.)- Published
- 2017
- Full Text
- View/download PDF
33. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression.
- Author
-
Verdonk K, Saleh L, Lankhorst S, Smilde JE, van Ingen MM, Garrelds IM, Friesema EC, Russcher H, van den Meiracker AH, Visser W, and Danser AH
- Subjects
- Adult, Case-Control Studies, Creatinine blood, Endothelin-1 metabolism, Female, Humans, Placental Circulation physiology, Pregnancy, Reference Values, Renin blood, Renin metabolism, Renin-Angiotensin System drug effects, Risk Assessment, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Endothelin-1 blood, Pre-Eclampsia metabolism, Pre-Eclampsia physiopathology, Pregnancy Outcome, Renin-Angiotensin System physiology
- Abstract
Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT2 receptors., (© 2015 American Heart Association, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
34. Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R study.
- Author
-
Korevaar TI, Steegers EA, Schalekamp-Timmermans S, Ligthart S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM, Hofman A, Hooijkaas H, Bongers-Schokking JJ, Russcher H, Tiemeier H, Jaddoe VW, Visser TJ, Medici M, and Peeters RP
- Subjects
- Feedback, Physiological physiology, Female, Fetal Blood, Gestational Age, Humans, Hyperthyroidism embryology, Hyperthyroidism physiopathology, Hypothyroidism embryology, Hypothyroidism physiopathology, Infant, Newborn, Male, Placenta Growth Factor, Pregnancy, Risk Assessment, Solubility, Thyroid Gland abnormalities, Thyrotropin blood, Thyroxine blood, Hyperthyroidism blood, Hypothyroidism blood, Pregnancy Proteins blood, Thyroid Gland physiology, Vascular Endothelial Growth Factor Receptor-1 blood
- Abstract
Context: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function., Design, Setting, and Participants: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates., Results: sFlt1 levels were positively associated with TSH (β 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (β -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (β 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01)., Conclusion: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.
- Published
- 2014
- Full Text
- View/download PDF
35. Air pollution exposure and markers of placental growth and function: the generation R study.
- Author
-
van den Hooven EH, Pierik FH, de Kluizenaar Y, Hofman A, van Ratingen SW, Zandveld PY, Russcher H, Lindemans J, Miedema HM, Steegers EA, and Jaddoe VW
- Subjects
- Cities, Cohort Studies, Female, Fetal Blood chemistry, Humans, Infant, Low Birth Weight, Infant, Newborn, Maternal Exposure, Netherlands, Particle Size, Placenta Growth Factor, Pregnancy, Pregnancy Proteins blood, Prospective Studies, Risk Factors, Ultrasonography, Doppler, Ultrasonography, Prenatal, Vascular Endothelial Growth Factor Receptor-1 blood, Vascular Resistance drug effects, Air Pollutants toxicity, Birth Weight drug effects, Fetal Development drug effects, Nitrogen Dioxide toxicity, Particulate Matter toxicity
- Abstract
Background: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications., Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands., Methods: We estimated levels of particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second-trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records., Results: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-µg/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (-11.8 g; 95% CI: -20.9, -2.7, and -10.7 g; 95% CI: -19.0, -2.4, respectively, per 10-µg/m3 increase in the prior 2 months), but not with placenta to birth weight ratio., Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal and fetal consequences.
- Published
- 2012
- Full Text
- View/download PDF
36. The Mediterranean diet and fetal size parameters: the Generation R Study.
- Author
-
Timmermans S, Steegers-Theunissen RP, Vujkovic M, den Breeijen H, Russcher H, Lindemans J, Mackenbach J, Hofman A, Lesaffre EE, Jaddoe VV, and Steegers EA
- Subjects
- Adult, C-Reactive Protein metabolism, Energy Intake, Female, Fetal Growth Retardation prevention & control, Folic Acid blood, Homocysteine blood, Humans, Logistic Models, Netherlands, Organ Size, Pregnancy, Prospective Studies, Qualitative Research, Surveys and Questionnaires, Vitamin B 12 blood, White People, Birth Weight, Diet, Mediterranean, Feeding Behavior, Fetal Development, Patient Compliance, Placenta, Prenatal Nutritional Physiological Phenomena
- Abstract
Developmental adaptations due to early nutritional exposures may have permanent health consequences. Studies of diet and fetal size have mainly focused on individual nutrients despite evidence that the pattern of food consumption may be of significance. Hence, we evaluated the associations of dietary habits in early pregnancy (gestational age < 18 weeks) with fetal size, uteroplacental vascular resistance, placental weight and birth weight in a prospective observational study of 3207 Caucasian pregnant mothers in Rotterdam, the Netherlands. Participants completed a semiquantitative FFQ during early pregnancy. Logistic regression analysis was used to predict the occurrence of intra-uterine growth retardation at birth as a function of food intake. The derived solution was considered as the dietary pattern. As it was characterised by higher intakes of fruit, vegetables, vegetable oil, fish, pasta and rice, and lower intakes of meat, potatoes and fatty sauces, it was labelled the 'Mediterranean' diet. The degree of adherence to the diet was positively associated with plasma folate and serum vitamin B12 concentrations and showed an inverse relationship with homocysteine and high-sensitivity C-reactive protein plasma concentrations (P <0·05). Important fetal size and placental parameters were associated with the degree of adherence to the diet, revealing a 72 g lower birth weight (95% CI -110·8, -33·3) and a 15 g lower placental weight (95% CI -29·8, -0·2) for women with low adherence to the diet. To conclude, low adherence to a Mediterranean diet in early pregnancy seems associated with decreased intra-uterine size with a lower placental and a lower birth weight.
- Published
- 2012
- Full Text
- View/download PDF
37. Chronic air pollution exposure during pregnancy and maternal and fetal C-reactive protein levels: the Generation R Study.
- Author
-
van den Hooven EH, de Kluizenaar Y, Pierik FH, Hofman A, van Ratingen SW, Zandveld PY, Lindemans J, Russcher H, Steegers EA, Miedema HM, and Jaddoe VW
- Subjects
- Adolescent, Adult, Cohort Studies, Female, Humans, Middle Aged, Netherlands, Particle Size, Pregnancy, Young Adult, Air Pollutants toxicity, C-Reactive Protein metabolism, Environmental Exposure, Fetus metabolism
- Abstract
Background: Exposure to air pollution has been associated with higher C-reactive protein (CRP) levels, suggesting an inflammatory response. Not much is known about this association in pregnancy., Objectives: We investigated the associations of air pollution exposure during pregnancy with maternal and fetal CRP levels in a population-based cohort study in the Netherlands., Methods: Particulate matter (PM) with an aerodynamic diameter ≤ 10 μm (PM10) and nitrogen dioxide (NO2) levels were estimated at the home address using dispersion modeling for different averaging periods preceding the blood sampling (1 week, 2 weeks, 4 weeks, and total pregnancy). High-sensitivity CRP levels were measured in maternal blood samples in early pregnancy (n = 5,067) and in fetal cord blood samples at birth (n = 4,450)., Results: Compared with the lowest quartile, higher PM10 exposure levels for the prior 1 and 2 weeks were associated with elevated maternal CRP levels (> 8 mg/L) in the first trimester [fourth PM10 quartile for the prior week: odds ratio (OR), 1.32; 95% confidence interval (CI): 1.08, 1.61; third PM10 quartile for the prior 2 weeks: OR, 1.28; 95% CI: 1.06, 1.56]; however, no clear dose-response relationships were observed. PM10 and NO2 exposure levels for 1, 2, and 4 weeks preceding delivery were not consistently associated with fetal CRP levels at delivery. Higher long-term PM10 and NO2 exposure levels (total pregnancy) were associated with elevated fetal CRP levels (> 1 mg/L) at delivery (fourth quartile PM10: OR, 2.18; 95% CI: 1.08, 4.38; fourth quartile NO2: OR, 3.42; 95% CI: 1.36, 8.58; p-values for trend < 0.05)., Conclusions: Our results suggest that exposure to air pollution during pregnancy may lead to maternal and fetal inflammatory responses.
- Published
- 2012
- Full Text
- View/download PDF
38. Falsely elevated lactate in severe ethylene glycol intoxication.
- Author
-
Sandberg Y, Rood PP, Russcher H, Zwaans JJ, Weige JD, and van Daele PL
- Subjects
- Acidosis, Lactic diagnosis, Acidosis, Lactic therapy, Adult, Blood Gas Analysis, Diagnosis, Differential, False Positive Reactions, Humans, Lactic Acid metabolism, Male, Psychotic Disorders, Substance-Related Disorders, Acidosis, Lactic chemically induced, Ethanol therapeutic use, Ethylene Glycol poisoning, Lactic Acid blood, Renal Dialysis, Solvents therapeutic use
- Abstract
A 29-year-old male presented at the emergency department of our hospital in a confused state. He had a history of psychoses and substance abuse. Physical examination revealed hyperventilation and abdominal tenderness. Blood gas analysis in the emergency department using an ABL 725 Radiometer analyser showed a severe metabolic acidosis with massive lactate elevation. Lactate acidosis due to mesenteric ischaemia was suspected. However, toxicology screening demonstrated ethylene glycol intoxication. Treatment with ethanol infusion and acute haemodialysis was started. Repeated laboratory measurements using a clinical chemistry analyser showed minimal plasma lactate elevation. Falsely elevated lactate measurement is a little known phenomenon that can occur in ethylene glycol intoxication and can cause serious delay in diagnosis. Therefore, elevated lactate concentrations measured on intensive care unit and emergency department blood gas analysers should be confirmed by a clinical chemistry analyser in the main laboratory in case of suspected ethylene glycol intoxication.
- Published
- 2010
39. Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene.
- Author
-
Russcher H, Dalm VA, de Jong FH, Brinkmann AO, Hofland LJ, Lamberts SW, and Koper JW
- Subjects
- Cell Line, Transformed, Exons, Gene Expression Regulation physiology, Humans, Organ Specificity, Protein Isoforms biosynthesis, Protein Isoforms genetics, Receptors, Glucocorticoid biosynthesis, Alternative Splicing genetics, Promoter Regions, Genetic, Receptors, Glucocorticoid genetics
- Abstract
The glucocorticoid receptor (GR) is widely expressed in various tissues throughout the human body. At least three different 3'-splice variants of the GR have been reported: GR-alpha, which is functionally active; GR-beta, which is a dominant negative inhibitor of GR-alpha function; and GR-P, which is thought to activate the function of GR-alpha. At least seven different variants for exon 1 exist, 1A-1F and 1H, each with its own promoter. In this study, we explored if tissue-specific splicing of the 3'-end variants of the GR is influenced by alternative promoter usage. cDNAs of different tissues and cell lines were used to investigate which part of transcripts carrying each of the three major variants for exons 1, 1A, 1B, or 1C, encodes for the splice variants GR-alpha, GR-beta, and GR-P. Our data demonstrate that the expression of GR-alpha is preferentially regulated by promoter 1C and that for the expression of GR-P promoter 1B is predominantly used. This indicates that regulation of GR splice variants could partly occur through selective use of the multiple promoters, and that this is another way to sensitize cells and tissues to the different activities of the GR isoforms.
- Published
- 2007
- Full Text
- View/download PDF
40. Glucocorticoid receptor polymorphism affects transrepression but not transactivation.
- Author
-
van den Akker EL, Russcher H, van Rossum EF, Brinkmann AO, de Jong FH, Hokken A, Pols HA, Koper JW, and Lamberts SW
- Subjects
- Aged, Aging, Body Mass Index, C-Reactive Protein analysis, Cohort Studies, Cross-Sectional Studies, Dexamethasone, Down-Regulation genetics, Female, Gene Expression, Genotype, Glucocorticoids pharmacology, Heterozygote, Humans, Hydrocortisone blood, Insulin Resistance, Interleukin-2 genetics, Leucine Zippers genetics, Male, Transcriptional Activation genetics, Waist-Hip Ratio, Gene Expression Regulation genetics, Polymorphism, Genetic genetics, Receptors, Glucocorticoid genetics
- Abstract
Context: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC transactivation of gene expression., Objective: The objective of the study was to investigate the effect of the GC receptor haplotype, characterized by the GR-9beta polymorphism, on GC transactivation and transrepression., Design and Methods: This was a cross-sectional study in 216 persons randomly selected from participants in The Rotterdam Study, a population-based cohort study in the elderly. Clinical and biochemical parameters of GC sensitivity were measured: weight, height, waist to hip ratio, glucose, insulin, total cholesterol, high-density lipoprotein, and C-reactive protein. In a dexamethasone suppression test, the response of serum cortisol concentrations was studied. Genotyping for four GC receptor polymorphisms was performed. In addition, ex vivo experiments were performed with leukocytes of 10 healthy controls and two persons homozygous for the GR-9beta polymorphism, in which the expression of two GC-sensitive genes, GC-induced leucine zipper and IL-2, was measured., Results: Persons carrying the GR-9beta haplotype without 22/23EK (n = 53) revealed no significant differences in their body mass index, waist to hip ratio, fat spectrum, and insulin sensitivity or in their cortisol response to dexamethasone and levels of C-reactive protein, compared with noncarriers (n = 113). Ex vivo, GC-induced up-regulation of GC-induced leucine zipper mRNA via transactivation did not significantly differ in GR-9beta homozygotes, whereas the down-regulation of IL-2 expression via transrepression was decreased., Conclusion: Persons carrying the GR-9beta haplotype seem to have a decreased GC transrepression with normal transactivation.
- Published
- 2006
- Full Text
- View/download PDF
41. Strategies for the characterization of disorders in cortisol sensitivity.
- Author
-
Russcher H, Smit P, van Rossum EF, van den Akker EL, Brinkmann AO, de Heide LJ, de Jong FH, Koper JW, and Lamberts SW
- Subjects
- Adolescent, Adrenal Cortex Diseases genetics, Adrenal Cortex Diseases pathology, Adult, B-Lymphocytes metabolism, B-Lymphocytes virology, Cell Line, Transformed, Cell Transformation, Viral, DNA chemistry, DNA genetics, Female, Gene Dosage, Humans, Male, Polymorphism, Single Nucleotide, Receptors, Glucocorticoid genetics, Sequence Analysis, DNA, Adrenal Cortex Diseases metabolism, Glucocorticoids metabolism, Hydrocortisone metabolism, Receptors, Glucocorticoid metabolism
- Abstract
Context: The clinical presentation of abnormalities in glucocorticoid (GC) sensitivity is diverse, and therefore it is difficult to diagnose this condition., Objective and Design: The objective of the study was to develop strategies for the characterization of GC sensitivity disorders., Setting: The study was conducted in an outpatient clinic., Patients: Nine patients with GC sensitivity disorders participated., Interventions: Sequence analysis of the GC receptor (GR), determination of GR number per cell, GR ligand-binding affinity, and GR splice regulation were performed in freshly prepared peripheral blood mononuclear lymphocytes and Epstein-Barr virus-transformed lymphoblasts. Cellular GC sensitivity was determined ex vivo by measuring the effect of dexamethasone on GC-induced leucine-zipper and IL-2 mRNA levels and on cell proliferation., Results: Differences in GR number per cell, GR affinity, GR splice variants, and effects on transactivation or transrepression of GC-sensitive genes were observed between patients and controls. Epstein-Barr virus transformation of lymphoblasts had no influence on GR affinity but increased the GR number 5-fold in healthy controls. In patients diagnosed as cortisol resistant, however, GR number after transformation was increased significantly less than 5-fold, whereas a higher GR number was observed in a patient suspected of cortisol hypersensitivity., Conclusion: This study illustrates several strategies to define abnormalities in GC sensitivity by describing nine patients with affected GC sensitivity, all with a unique clinical course and background.
- Published
- 2006
- Full Text
- View/download PDF
42. Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.
- Author
-
Russcher H, Smit P, van den Akker EL, van Rossum EF, Brinkmann AO, de Jong FH, Lamberts SW, and Koper JW
- Subjects
- Animals, Blotting, Western, COS Cells, Cells, Cultured, Chlorocebus aethiops, DNA Primers genetics, Dexamethasone pharmacology, Genetic Variation, Interleukin-2 biosynthesis, Interleukin-2 genetics, Luciferases genetics, Plasmids genetics, RNA biosynthesis, RNA isolation & purification, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors biosynthesis, Transcription Factors genetics, Transfection, Gene Expression Regulation physiology, Polymorphism, Genetic genetics, Receptors, Glucocorticoid genetics
- Abstract
Context: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively., Objective and Design: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor kappaB-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR., Results: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (-14 +/- 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: -48 +/- 6%, P < 0.01, n = 1; heterozygous: -21 +/- 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 +/- 3%; P < 0.02) and ex vivo (homozygous: 204 +/- 19%, P < 0.0001, n = 1; heterozygous: 124 +/- 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR., Conclusion: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.
- Published
- 2005
- Full Text
- View/download PDF
43. Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism.
- Author
-
Russcher H, van Rossum EF, de Jong FH, Brinkmann AO, Lamberts SW, and Koper JW
- Subjects
- Alternative Splicing genetics, Animals, Arginine genetics, Base Sequence, COS Cells, Chlorocebus aethiops, Codon, Initiator genetics, Dexamethasone metabolism, Humans, Lysine genetics, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Peptide Chain Initiation, Translational, Protein Isoforms genetics, Protein Isoforms physiology, RNA, Messenger analysis, RNA, Messenger metabolism, Receptors, Glucocorticoid metabolism, Transcription, Genetic, Transcriptional Activation genetics, Polymorphism, Genetic, Receptors, Glucocorticoid genetics
- Abstract
One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not affected. These results show that the transcriptional activity in GR(ER22/23EK) carriers is decreased because more of the less transcriptionally active GR-A isoform is formed. This is probably caused by altered secondary mRNA structure.
- Published
- 2005
- Full Text
- View/download PDF
44. Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2.
- Author
-
Smit P, Russcher H, de Jong FH, Brinkmann AO, Lamberts SW, and Koper JW
- Subjects
- Dexamethasone pharmacology, Humans, Hydrocortisone blood, Male, Middle Aged, Receptors, Glucocorticoid physiology, Transcriptional Activation, Gene Expression Regulation drug effects, Glucocorticoids pharmacology, Interleukin-2 genetics, Transcription Factors genetics
- Abstract
Individual glucocorticoid (GC) sensitivity was determined by measuring the effects of several clinically used GCs on transactivation of the GC-induced leucine zipper (GILZ) gene and on transrepression of the IL-2 gene using quantitative real-time PCR. A clear difference in relative potencies for transactivation and transrepression of the various GCs was observed, suggesting differential effects. To determine whether the in vitro outcomes could predict in vivo effects of GCs, 15 individuals underwent a 0.25-mg dexamethasone (DEX) suppression test (DST) while determining GILZ and IL-2 mRNA levels in their peripheral blood mononuclear cells incubated with hydrocortisone, DEX, budesonide, and prednisolone. No correlations were found between the DST and the two expression assays. However, significant correlations existed between hydrocortisone and DEX (r = 0.52; P = 0.046), hydrocortisone and budesonide (r = 0.48; P = 0.069), and hydrocortisone and prednisolone (r = 0.86; P = 0.007) regarding GILZ mRNA levels, and between hydrocortisone and DEX (r = 0.62; P = 0.014), hydrocortisone and budesonide (r = 0.71; P = 0.003), and hydrocortisone and prednisolone (r = 0.71; P = 0.047) regarding IL-2 mRNA levels. In conclusion, intra- and inter-individual variations in GC sensitivity were observed using two expression assays representing GC-mediated transactivation and transrepression. The two expression assays did not correlate with each other or with the results of the DST. This suggests that regulation of the hypothalamic-pituitary-adrenal axis is more complex. However, within an individual person, these two tests combined might predict what type and dosage of GC will be preferable in individual patients for its inhibitory clinical effects, together with relatively fewer transactivating effects related to adverse effects.
- Published
- 2005
- Full Text
- View/download PDF
45. Identification and characterization of two unusual cGMP-stimulated phoshodiesterases in dictyostelium.
- Author
-
Bosgraaf L, Russcher H, Snippe H, Bader S, Wind J, and Van Haastert PJ
- Subjects
- 3',5'-Cyclic-GMP Phosphodiesterases chemistry, 3',5'-Cyclic-GMP Phosphodiesterases genetics, Amino Acid Sequence, Animals, Cyclic AMP metabolism, Cyclic GMP metabolism, Dictyostelium cytology, Dictyostelium genetics, Dictyostelium physiology, Gene Targeting, Humans, Molecular Sequence Data, Phenotype, Protein Structure, Tertiary, Sequence Alignment, 3',5'-Cyclic-GMP Phosphodiesterases metabolism, Dictyostelium enzymology
- Abstract
Recently, we recognized two genes, gbpA and gbpB, encoding putative cGMP-binding proteins with a Zn(2+)-hydrolase domain and two cyclic nucleotide binding domains. The Zn(2+)-hydrolase domains belong to the superfamily of beta-lactamases, also harboring a small family of class II phosphodiesterases from bacteria and lower eukaryotes. Gene inactivation and overexpression studies demonstrate that gbpA encodes the cGMP-stimulated cGMP-phosphodiesterase that was characterized biochemically previously and was shown to be involved in chemotaxis. cAMP neither activates nor is a substrate of GbpA. The gbpB gene is expressed mainly in the multicellular stage and seems to encode a dual specificity phosphodiesterase with preference for cAMP. The enzyme hydrolyses cAMP approximately 9-fold faster than cGMP and is activated by cAMP and cGMP with a K(A) value of approximately 0.7 and 2.3 microM, respectively. Cells with a deletion of the gbpB gene have increased basal and receptor stimulated cAMP levels and are sporogeneous. We propose that GbpA and GbpB hydrolyze the substrate in the Zn(2+)-hydrolase domain, whereas the cyclic nucleotide binding domains mediate activation. The human cGMP-stimulated cAMP/cGMP phosphodiesterase has similar biochemical properties, but a completely different topology: hydrolysis takes place by a class I catalytic domain and GAF domains mediate cGMP activation.
- Published
- 2002
- Full Text
- View/download PDF
46. A novel cGMP signalling pathway mediating myosin phosphorylation and chemotaxis in Dictyostelium.
- Author
-
Bosgraaf L, Russcher H, Smith JL, Wessels D, Soll DR, and Van Haastert PJ
- Subjects
- 3',5'-Cyclic-AMP Phosphodiesterases genetics, 3',5'-Cyclic-AMP Phosphodiesterases metabolism, Animals, Carrier Proteins metabolism, Chemotaxis physiology, Cytoskeleton metabolism, Dictyostelium drug effects, Dictyostelium genetics, Guanylate Cyclase genetics, Guanylate Cyclase metabolism, Phosphorylation, Protein Processing, Post-Translational, Protozoan Proteins genetics, Cyclic GMP physiology, Dictyostelium physiology, Intracellular Signaling Peptides and Proteins, Myosin Type II metabolism, Protozoan Proteins metabolism, Second Messenger Systems physiology
- Abstract
Chemotactic stimulation of Dictyostelium cells results in a transient increase in cGMP levels, and transient phosphorylation of myosin II heavy and regulatory light chains. In Dictyostelium, two guanylyl cyclases and four candidate cGMP-binding proteins (GbpA- GbpD) are implicated in cGMP signalling. GbpA and GbpB are homologous proteins with a Zn2+-hydrolase domain. A double gbpA/gbpB gene disruption leads to a reduction of cGMP-phosphodiesterase activity and a 10-fold increase of basal and stimulated cGMP levels. Chemotaxis in gbpA(-)B(-) cells is associated with increased myosin II phosphorylation compared with wild-type cells; formation of lateral pseudopodia is suppressed resulting in enhanced chemotaxis. GbpC is homologous to GbpD, and contains Ras, MAPKKK and Ras-GEF domains. Inactivation of the gbp genes indicates that only GbpC harbours high affinity cGMP-binding activity. Myosin phosphorylation, assembly of myosin in the cytoskeleton as well as chemotaxis are severely impaired in mutants lacking GbpC and GbpD, or mutants lacking both guanylyl cyclases. Thus, a novel cGMP signalling cascade is critical for chemotaxis in Dictyostelium, and plays a major role in myosin II regulation during this process.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.