Publications by authors named "Irmgard Classen-Linke"

13 Publications

  • Page 1 of 1

Endometrial Dating Method Detects Individual Maturation Sequences During the Secretory Phase.

In Vivo 2020 Jul-Aug;34(4):1951-1963

Fertility-Center Munich, Munich, Germany.

Background/aim: This study assessed whether a new immunohistochemical dating method allows precise endometrial dating allowing optimal timing for embryo transfer.

Patients And Methods: A novel method was used for endometrial dating, with parameters including menstrual cycle days, Noyes histological criteria, along with immunohistochemical expression pattern of estrogen and progesterone receptors and proliferation marker Ki-67. Endometrial maturation was analyzed on days +5 to +10 after ovulation or progesterone administration in 217 biopsies from 151 subfertile patients during the secretory phase.

Results: Endometrial maturation varied individually, occurring 1.68±1.67 days late. Comparison of histological maturation with clinical days after ovulation showed a delay of about 2 days.

Conclusion: Endometrial maturation requires 8 days, rather than the expected 6 days, to reach the histological mid-secretory phase. This is not a delay and is also seen in fertile patients. The new analysis method used is superior to that using Noyes criteria alone and provides a better basis for determining conditions for optimal timing of embryo transfers.
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http://dx.doi.org/10.21873/invivo.11992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439867PMC
April 2020

Ultrastructural changes in endometrial desmosomes of desmoglein 2 mutant mice.

Cell Tissue Res 2018 Nov 25;374(2):317-327. Epub 2018 Jun 25.

Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.

The intercellular binding of desmosomal junctions is mediated by cadherins of the desmoglein (Dsg) and desmocollin (Dsc) type. Dsg2 mutant mice with deletion of a substantial segment of the extracellular EC1-EC2 domain, which is believed to participate in homo- and heterophilic desmosomal cadherin interactions, develop cardiac fibrosis and ventricular dilation. Widening of the intercellular cleft and complete intercalated disc ruptures can be observed in the hearts of these mice. Since a reduced litter size of homozygous Dsg2 mutant mice was noted and a functional correlation between desmosomes and embryo implantation has been deduced from animal studies, we looked for an alteration of desmosomes in uterine endometrial epithelium. Shape and number of desmosomes as well as the expression of Dsg2 and the desmosomal plaque protein desmoplakin (Dsp) were investigated by electron microscopy and immunohistochemistry in 12 oestrous-dated mice (7 wild type and 5 homozygous Dsg2 mutant mice) at the age of 9-17 weeks. The immunohistochemical detection of Dsg2 was diminished in the mutants and the number of desmosomes was significantly reduced as revealed by electron microscopy. In addition, the intercellular desmosomal space measured in electron micrographs was considerably widened in the Dsg2 mutants. The increased intercellular spacing can be explained by the partial deletion of the extracellular EC1-EC2 domain of Dsg2. Whether these changes explain the reduced number of offspring of homozygous Dsg2 mutant mice remains to be further investigated.
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http://dx.doi.org/10.1007/s00441-018-2869-zDOI Listing
November 2018

Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients?

Geburtshilfe Frauenheilkd 2017 Jul 17;77(7):756-764. Epub 2017 Jul 17.

Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Introduction: This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected.

Methods: To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity - β integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs).

Results: The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase.

Conclusions: It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules.
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http://dx.doi.org/10.1055/s-0043-111899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514021PMC
July 2017

Anatomy meets dentistry! Linking anatomy and clinical practice in the preclinical dental curriculum.

BMC Med Educ 2016 Nov 25;16(1):305. Epub 2016 Nov 25.

Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Wendlingweg 2, Aachen, 52074, Germany.

Background: Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on "Palpation of the Head and Neck Muscles" and to measure the learning outcomes.

Methods: For the curricular development of the expanded course module, Kern's 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module) on learning outcomes. Four learning methods were compared: (1) lecture, (2) lecture + e-module, (3) lecture + skills training, (4) lecture + skills training + e-module. An objective structured clinical examination (OSCE) was used to measure and compare learning outcomes.

Results: The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007). Students who participated in the skills training did better (φ 107.4 ± 14.4 points) than students who only attended the lecture (φ 88.8 ± 26.2 points). Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points) than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points), thus making it the ideal method for achieving the learning objectives defined in this study.

Conclusions: The "Palpation of the Head and Neck Muscles" interdisciplinary skills training course linking basic anatomical knowledge and clinical skills led to clearly improved learning outcomes for both, anatomical knowledge and clinical skills. The additional use of an e-learning tool (e-module) improved the learning effect.
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http://dx.doi.org/10.1186/s12909-016-0825-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123369PMC
November 2016

Altered expression of progesterone receptor isoforms A and B in human eutopic endometrium in endometriosis patients.

Ann Anat 2016 Jul 2;206:1-6. Epub 2016 Apr 2.

Institute of Molecular and Cellular Anatomy, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany. Electronic address:

Recent data implicate an altered expression of progesterone receptor isoform A (PR-A) and B (PR-B) in the endometrium of endometriosis patients. This prospective exploratory study aimed to precisely determine the PR-A and PR-B expression using immunohistochemical techniques in eutopic endometrium of women with endometriosis compared with disease-free women throughout the menstrual cycle. All symptomatic patients underwent laparoscopy for the diagnosis of endometriosis and histological confirmation of the disease (EO) whereas controls were proven disease-free (CO). In CO samples (n=10) an increased expression of PR-A and PR-B during the proliferative to early secretory phase and a decreased expression of both receptor isoforms during the mid to late secretory phase was ascertained in accordance with previous studies. In patients with endometriosis (n=16) no cycle dependent pattern of PR-A and PR-B expression was identified in contrast to patients without endometriosis. Moreover, in EO samples a huge variety of inter- and intra-individual differences in PR-A and PR-B expression were detected. These data provide further evidence that dysregulation of the PR-A and PR-B expression might contribute to the pathophysiology of endometriosis.
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http://dx.doi.org/10.1016/j.aanat.2016.03.004DOI Listing
July 2016

Effects of xenon and isoflurane on apoptosis and inflammation in a porcine myocardial infarction model.

Ann Anat 2013 Mar 12;195(2):166-74. Epub 2012 Sep 12.

Department of Anaesthesiology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany.

Volatile anaesthetics can reduce the infarction size in myocardial tissue when administered before and during experimentally induced ischaemia. The aim of this study was to investigate whether xenon is beneficial compared to isoflurane in limiting myocardial tissue apoptosis and inflammation induced by experimental ischaemia-reperfusion injury in a porcine right ventricular infarction model. Twenty-one animals used for this study randomly received isoflurane, xenon or thiopental, (n=6-8 per group). Myocardial infarction was induced for 90min, followed by reperfusion for 120min. Tissues from the left and right ventricles were removed from the sites of infarction, reperfusion and remote areas, and processed for immunohistochemistry. Apoptosis (caspase-3 staining) and neutrophilic infiltration (naphthol AS-D chloroacetate-specific esterase) were assessed and evaluated. Statistical analysis was performed using an ANOVA of repeated measures. Density of apoptotic cells were higher in tissues from animals that were anesthetized with xenon. This effect was significant in comparison to isoflurane (p=0.0177). Neutrophilic infiltration was significantly higher in the right compared to the left ventricle (p<0.001), whereas no significant differences in the number of granulocytes based on the anaesthetic regime or the different tissue areas were found. We conclude that xenon, in the early phase of ischaemia and reperfusion, induces a significant increase in apoptosis compared to isoflurane. Therefore, clinical use of this anaesthetic in cardiocompromised patients should be taken with care until more long-term studies have been carried out. The increased neutrophilic infiltration in the right vs. the left ventricle indicates the right ventricle being more susceptible to ischaemia-reperfusion injury.
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http://dx.doi.org/10.1016/j.aanat.2012.07.013DOI Listing
March 2013

Mammaglobin 1: not only a breast-specific and tumour-specific marker, but also a hormone-responsive endometrial protein.

Histopathology 2012 Nov 20;61(5):955-65. Epub 2012 Sep 20.

Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Aims: The secretoglobin mammaglobin 1 (MGB1) is strongly expressed in breast tumours, and is therefore used to detect breast cancer metastases, although it has also been detected in other tissues. The aim of this study was to examine MGB1 expression and its hormonal regulation in human endometrium to further investigate the use of MGB1 as a marker molecule.

Methods And Results: Mammaglobin 1 expression was assessed immunohistochemically in endometrial samples from 60 normal fertile patients throughout the menstrual cycle, in 49 endometriotic tissue samples, in 15 endometrial adenocarcinomas, and in 36 breast carcinomas. In addition, 25 endometrial samples were analysed by western blot and quantitative real-time reverse transcription polymerase chain reaction. To prove hormonal regulation, primary endometrial epithelial cells were cultured with 17β-oestradiol and promegestone. MGB1 was detected in human endometrial tissue, with peak expression during the luteal phase, in 31% of endometriotic samples, in 53% of endometrial adenocarcinomas, and in 64% of breast carcinomas. MGB1 mRNA expression was increased in vitro by hormonal treatment.

Conclusions: Our data show that MGB1 expression is not restricted to normal and malignant breast tissue. Besides its documented occurrence in endometriotic and malignant endometrial tissues, MGB1 is also expressed in normal human endometrium, and such expression is controlled by steroid hormones.
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http://dx.doi.org/10.1111/j.1365-2559.2012.04290.xDOI Listing
November 2012

Redistribution of adhering junctions in human endometrial epithelial cells during the implantation window of the menstrual cycle.

Histochem Cell Biol 2012 Jun 12;137(6):777-90. Epub 2012 Feb 12.

Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.

The human uterine epithelium is characterised by remarkable plasticity with cyclic changes in differentiation that are controlled by ovarian steroid hormones to optimise conditions for embryo implantation. To understand whether and how cell-cell adhesion is affected, the localisation of junction proteins was studied throughout the menstrual cycle. Expression patterns were examined by immunofluorescence in 36 human endometrial specimens of different cycle stages. Antibodies against the desmosomal proteins desmoplakin 1/2 (Dp 1/2) and desmoglein 2 (Dsg 2), the adherens junction proteins E-cadherin and β-catenin and also the common junctional linker protein plakoglobin showed a strong subapical staining during the proliferative phase until the early luteal phase (day 20). In the mid- to late luteal phase, however, these junctional proteins redistributed over the entire lateral plasma membranes. In contrast, tight junction proteins (ZO-1, claudin 4) remained at their characteristic subapical position throughout the menstrual cycle. mRNA levels of Dp 1/2, E-cadherin and ZO-1 obtained by real time RT-PCR were not significantly changed during the menstrual cycle. The observed redistribution of desmosomes and adherens junctions coincides with the onset of the so called implantation window of human endometrium. We propose that this change is controlled by ovarian steroids and prepares the endometrium for successful trophoblast invasion.
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http://dx.doi.org/10.1007/s00418-012-0929-0DOI Listing
June 2012

Class I histone deacetylase expression in the human cyclic endometrium and endometrial adenocarcinomas.

Hum Reprod 2007 Nov 29;22(11):2956-66. Epub 2007 Aug 29.

Department of Anatomy and Reproductive Biology, RWTH University of Aachen, Wendlingweg 2, 52074, Aachen, Germany.

Background: Class I histone deacetylases (HDACs) and acetylases (HATs) are members of transcriptional pre-initiation complexes assembled by steroid hormone receptors. Recently, HDAC inhibitors were shown to enhance differentiation of endometrial fibroblasts and endometrial adenocarcinomas. However, there is only rare information on HDAC and HAT expression in the human endometrium.

Methods: HDAC-1, -2, -3 and HAT (PCAF and GCN5) mRNA expression was studied in tissue from premenopausal women undergoing hysterectomy by real-time or semiquantitative RT-PCR. HDAC protein expression was assessed by Western Blot and immunohistochemistry. In endometrial adenocarcinomas (n = 17), HDAC-1 expression was studied by immunohistochemistry.

Results: In the human endometrium, HDAC-1, -2, -3 and PCAF mRNA are expressed without cyclical changes. Western blot analysis demonstrated that HDAC-2 protein expression was slightly, but significantly elevated in the secretory phase (P < 0.01 versus day 5-8), whereas HDAC-1 and -3 protein expression was constitutive throughout the menstrual cycle. By immunohistochemistry, nuclear expression of HDAC proteins was detected in all endometrial cell types. In the case of HDAC-3, immunostaining was significantly reduced in the endometrial surface epithelium on day 6-10 (P < 0.01 versus days 15-18 and 24-28). Compared to normal endometrium, a high proportion of endometrial adenocarcinomas showed impaired HDAC-1 protein expression in the epithelial and stromal compartment.

Conclusions: Class I HDACs and HATs are expressed in the human endometrium throughout the menstrual cycle, suggesting the cyclic endometrium as a potential target for HDAC inhibitors. We hypothesis that alterations of HDAC and/or HAT expression are potentially involved in impaired endometrial differentiation.
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http://dx.doi.org/10.1093/humrep/dem241DOI Listing
November 2007

Expression of leucine-rich repeat-containing G-protein-coupled receptors in the human cyclic endometrium.

Fertil Steril 2007 Jun 1;87(6):1428-37. Epub 2007 Feb 1.

Department of Anatomy and Reproductive Biology, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.

Objective: To study the mRNA expression of the two leucine-rich repeat-containing G-protein-coupled receptors LGR-4 and LGR-5 and the mRNA and protein expression of LGR-7, the relaxin receptor, in the human cyclic endometrium.

Design: Retrospective study.

Setting: Department of Anatomy and Reproductive Biology, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.

Method(s): LGR-4, -5, and -7 mRNA expression was assessed by semiquantitative and real time reverse transcription-polymerase chain reaction in the endometrium of premenopausal women (n = 26) and cultured primary endometrial epithelial cells and fibroblasts (n = 3). Transcript size was determined by Northern blotting. LGR-7 protein expression was assessed by immunohistochemistry.

Result(s): The mRNA of LGR-4, LGR-5, and LGR-7 was expressed constitutively throughout the menstrual cycle in the endometrium, and characterized by substantial differences in expression levels of individual women. LGR-7 immunostaining was detected in the epithelium of the functional layer throughout the cycle, with lowest staining in the midproliferative phase. Furthermore, individual stromal cells of the functional layer and the stroma of the basal layer showed LGR-7 immunostaining.

Conclusion(s): Endometrial expression of the mRNA of orphan receptors LGR-4 and LGR-5 implies that the endometrium is potentially influenced by as yet unknown mediators, which are possibly involved in fertility control. Furthermore, we confirmed constitutive endometrial mRNA expression of LGR-7, the classical relaxin receptor, and demonstrated specific LGR-7 immunostaining of different endometrial cell types, which suggests a physiological role of relaxin in the human endometrium.
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http://dx.doi.org/10.1016/j.fertnstert.2006.11.061DOI Listing
June 2007

Evaluation of a new approach to implement structured, evidence-based emergency medical care in undergraduate medical education in Germany.

Resuscitation 2005 Jun 18;65(3):345-56. Epub 2005 Apr 18.

Department of Anaesthesiology, University Hospital Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany.

Since June 2002, revised regulations in Germany allow medical faculties to implement new curricular concepts. The medical faculty of the Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Germany, decided to start a major reform experiment in winter 2003, focussing on an interdisciplinary integration of organs and organ systems such as the cardiovascular or respiratory system. Furthermore, students will have contact with patients at an early stage of their studies. Thus, re-organisation of course contents should lead to a chance to improve practical experience. With the public having the right to expect that physicians and all physicians in training possess a basic knowledge of emergency medical care and the necessary skills to manage acute problems, it was decided to start the first year of the Medical Reform Curriculum Aachen with 3 weeks interdisciplinary introduction into emergency medical care. The task consisted of defining interdisciplinary core objectives and the need to implement teaching and learning principles necessary for further education. Due to this, the content of this course should have practical relevance for the students concerning their practical experiences in the future. The result is an introductory course in emergency medical care in the first semester, coordinated with the lectures. Besides skill training on basics of emergency medical care (basic life support (BLS), early defibrillation), practical training in other lifesaving techniques (e.g., immobilisation skills) and basic principles of daily clinical care are included. In addition, personal safety and a standard algorithm for assessing the patient are covered by problem-based learning sessions. The course evaluation data clearly showed acceptance of the new approach and enhances possibilities of extending implementation of relevant topics concerning emergency medical care within the Medical Reform Curriculum Aachen.
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http://dx.doi.org/10.1016/j.resuscitation.2004.11.023DOI Listing
June 2005

Cytokine microenvironments in human first trimester decidua are dependent on trophoblast cells.

Fertil Steril 2003 May;79(5):1176-86

Department of Anatomy and Reproductive Biology, School of Medicine, RWTH University of Aachen, Aachen, Germany.

Objective: To compare cytokine expression profiles of decidua basalis (containing trophoblast cells) and decidua parietalis (without trophoblast cells) for determination of microenvironments in human first trimester decidua.

Design: Retrospective study.

Setting: School of Medicine, RWTH University of Aachen, Aachen Germany, and Bourgognekliniek Maastricht, Maastricht, The Netherlands.

Patient(s): Forty-six women who had undergone elective first-trimester termination of viable pregnancy at 5 to 12 weeks.

Main Outcome Measure(s): Quantitative cytokine protein analysis in decidual tissues by enzyme-linked immunosorbent assay, qualitative cytokine messenger (m)RNA analysis in isolated decidual cell samples, and comparative mRNA and protein analysis in tissues of decidua basalis compared with decidua parietalis.

Result(s): Interleukin-2, interferon-gamma (Th-1), interleukin-4 (Th-2), and interleukin-1beta proteins are expressed in the human first-trimester decidua. Interleukin-2, interferon-gamma, and interleukin-4 mRNA mainly derive from the decidual tissue leukocytes. Interleukin-1beta mRNA is expressed by all decidual cell types. Interferon-gamma mRNA and protein is detected predominantly in the decidua basalis, which contains trophoblast cells.

Conclusion(s): Microenvironments are established topographically by different expression of cytokines in decidua basalis and decidua parietalis. These locally specific patterns are indicative of fetomaternal cross-talk. Higher interferon-gamma concentrations in decidua basalis may influence leukocyte differentiation (e.g., macrophage activation) and trophoblast invasion (e.g., by induction of expression of major histocompatibility complex).
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http://dx.doi.org/10.1016/s0015-0282(02)04829-xDOI Listing
May 2003

Estrogen receptor alpha and progesterone receptor A and B concentration and localization in the lower uterine segment in term parturition.

J Soc Gynecol Investig 2002 Jul-Aug;9(4):226-32

Department of Obstetrics and Gynecology, University Hospital, Technical University, Aachen, Germany.

Objective: To determine the localization and concentrations of estrogen receptor alpha and progesterone receptors A and B in the lower uterine segment during term parturition.

Methods: Biopsies were taken from 70 patients during nonelective cesarean delivery. The patients were at different stages of cervical dilatation (<2 cm, 2-3.9 cm, 4-6 cm, >6 cm) and different duration of labor (< or =6 hours, >6-12 hours, >12 hours). The receptor concentrations were determined with solid phase immunoassays, and their localization was investigated immunohistochemically.

Results: Estrogen receptor alpha concentration decreased significantly from 2.12 fmol/mg protein at less than 2 cm dilatation to 1.08 fmol/mg (4-6 cm) but tended to increase at greater than 6 cm. Progesterone receptor A and B concentration was 84.7 fmol/mg at less than 2 cm dilatation, decreased significantly to 36.6 fmol/mg (2-3.9 cm), and increased again with further dilation. Concentrations of both receptors did not depend on duration of labor. By immunohistochemistry only progesterone receptor A and B was found to be expressed by endothelial and smooth muscle cells of the vessels, stromal fibroblasts, smooth muscle cells in the myometrium, and glandular epithelial cells. Regardless of the extent of cervical dilatation, expression of progesterone receptors A and B was marked.

Conclusion: A decrease in estrogen receptor alpha and progesterone receptor A and B concentration in the early phase of first stage labor may play a role in cervical dilation at term.
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December 2002