Helmholtz Institute for Biomedical Engineering

Aachen, Germany

Helmholtz Institute for Biomedical Engineering

Aachen, Germany
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Becker M.,RWTH Aachen | Roehl A.B.,RWTH Aachen | Siekmann U.,RWTH Aachen | Koch A.,German Naval Medical Institute | And 5 more authors.
Herz | Year: 2014

Seismocardiography (SCG) is a noninvasive technique for recording cardiac vibrations. Changes in these waves have been correlated with chronic and acute alterations in myocardial function. This analysis is complex and clinical integration limited. The current study aimed to simplify the utilization of SCG by fast Fourier transformation for a reliable discrimination between different intra- and postoperative causes of hypotension (i.e., myocardial ischemia or hypovolemia). We operated on nine pigs and recorded SCG at baseline, at hypovolemia (occlusion of the inferior vena cava), and at ischemia (occlusion of the right coronary artery). In conclusion, SCG enables detection and differentiation of ischemia and hypovolemia as important causes of altered myocardial function during and after surgery. Thus, this simple and noninvasive diagnostic tool may be used intra- and postoperatively to identify patients at risk. © 2013 Urban & Vogel.


Gusmao E.G.,RWTH Aachen | Dieterich C.,Max Planck Institute for Biology of Ageing | Zenke M.,RWTH Aachen | Zenke M.,Helmholtz Institute for Biomedical Engineering | And 2 more authors.
Bioinformatics | Year: 2014

Motivation: The identification of active transcriptional regulatory elements is crucial to understand regulatory networks driving cellular processes such as cell development and the onset of diseases. It has recently been shown that chromatin structure information, such as DNase I hypersensitivity (DHS) or histone modifications, significantly improves cell-specific predictions of transcription factor binding sites. However, no method has so far successfully combined both DHS and histone modification data to perform active binding site prediction.Results: We propose here a method based on hidden Markov models to integrate DHS and histone modifications occupancy for the detection of open chromatin regions and active binding sites. We have created a framework that includes treatment of genomic signals, model training and genome-wide application. In a comparative analysis, our method obtained a good trade-off between sensitivity versus specificity and superior area under the curve statistics than competing methods. Moreover, our technique does not require further training or sequence information to generate binding location predictions. Therefore, the method can be easily applied on new cell types and allow flexible downstream analysis such as de novo motif finding. © The Author 2014. Published by Oxford University Press. © The Author 2014. Published by Oxford University Press.


Lin Q.,RWTH Aachen | Wagner W.,Helmholtz Institute for Biomedical Engineering | Zenke M.,RWTH Aachen
Methods in Molecular Biology | Year: 2013

This chapter covers the genome-wide DNA methylation analysis using microarray platforms, such as Illumina Infinium HumanMethylation27 BeadChips or HumanMethylation450 BeadChips. Using our previously published ovarian cancer dataset (Bauerschlag et al., Oncology 80:12-20, 2011), we introduce the underlying design principles of these methylation array platforms and describe common yet effective bioinformatic strategies for data analysis, including data preprocessing, clustering methods, and differential methylation tests. We also describe the downstream analytic techniques for the results derived from the methylation array, i.e., gene set enrichment analysis and sequence-based motif analysis, which can be utilized for generating biological hypotheses. © Springer Science+Business Media, New York 2013.


Floehr J.,Helmholtz Institute for Biomedical Engineering | Dietzel E.,Helmholtz Institute for Biomedical Engineering | Neulen J.,RWTH Aachen | Rosing B.,RWTH Aachen | And 2 more authors.
Human Reproduction | Year: 2016

STUDY QUESTION Is serum fetuin-B associated with the fertilization rate in in vitro fertilization (IVF)? SUMMARY ANSWER Serum fetuin-B increased during IVF cycles when oocytes could be fertilized while remained unchanged in fertilization failure. WHAT IS KNOWN ALREADY Fetuin-B deficiency in mice causes premature zona pellucida hardening mediated by the zona protease ovastacin. Thus fetuin-B deficiency renders females infertile. STUDY DESIGN, SIZE, DURATION We determined the human serum fetuin-B reference range, studying longitudinally, over the course of one month, five male and seven female volunteers without hormone treatment and four female volunteers on varying hormonal contraception. We sampled blood and determined serum fetuin-B, luteinizing hormone (LH), estradiol (E2) and progesterone (P4). In addition, we determined serum fetuin-B and estradiol in eight women undergoing intracytoplasmatic sperm injection (ICSI, nine ICSI cycles) and 19 women undergoing IVF (21 IVF cycles) after ovarian stimulation with recombinant human follicular stimulating hormone (rFSH) and/or a combined medication of FSH and LH. At least three blood samples were analyzed in each cycle. We compared serum fetuin-B and follicular fluid fetuin-B in nine patients by measuring follicular fetuin-B in pooled follicular fluid, and in fluid obtained from individual follicles. Samples were drawn from January 2012 to March 2014. PARTICIPANTS/MATERIALS, SETTING, METHOD All volunteers and patients gave informed consent. Fetuin-B was measured employing a commercial sandwich enzyme-linked immunosorbent assay. Serum fetuin-B was determined as duplicates in 5 male (34 ± 14.6 years) and 11 female volunteers (29.4 ± 4.1 years) as well as in female volunteers on hormonal contraception (30.0 ± 6.5 years). The duplicate standard deviation was 4.0 ± 2.3%. The contraceptive drugs were mono or combined preparations containing 0-0.03 mg ethinyl estradiol, and 0.15-3.0 mg of various progestins. In addition, serum fetuin-B was determined as triplicates in 27 female patients undergoing conventional IVF (19) or ICSI (8). The triplicate standard deviation was 3.3 ± 1.8%. IVF was declared as 'successful', if at least one oocyte was fertilized, and 'unsuccessful', if no oocyte could be fertilized. Patient age was 34.4 ± 4.4 years in successful IVF, and 35.4 ± 3.3 years in unsuccessful IVF. Serum and follicular fluid of patients undergoing controlled ovarian hyperstimulation were analyzed. Serum was drawn at the day of follicle aspiration. MAIN RESULTS AND THE ROLE OF CHANCE Serum fetuin-B and follicular fluid fetuin-B were not significantly different in six out of nine patients suggesting, in principle, free exchange of fetuin-B between serum and follicular fluid. Thus serum fetuin-B may be used as a proxy of follicular fluid fetuin-B. Serum fetuin-B increased during successful IVF cycles (n = 15, P < 0.0001), but did not change in unsuccessful IVF cycles (n = 6, P = 0.118) despite increased estradiol levels (P = 0.0019 and P = 0.0254, respectively). LIMITATIONS, REASONS FOR CAUTION The female volunteers self-reported their respective hormone medication. Medication was verified by serum estradiol, LH and progesterone measurements. For oocyte harvesting, the vaginal wall was punctured once only to minimize co-morbidity. Low grade cross-contamination of individual follicular fluid aspirates and contamination of the follicular fluid with small amounts of blood were inevitable. Samples were routinely checked for the presence of hemoglobin that would suggest blood contamination. Only samples containing <250 erythrocyte equivalents/μl were used for analysis. WIDER IMPLICATIONS OF THE FINDING Serum fetuin-B may be used as a marker to predict the fertilization success in IVF. Fetuin-B levels attained during IVF stimulation may help to make an informed decision whether oocytes should be fertilized by IVF or by ICSI to overcome the zona pellucida as a barrier. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.


Muller M.C.,University of Bonn | Belei P.,Helmholtz Institute for Biomedical Engineering | De La Fuente M.,Helmholtz Institute for Biomedical Engineering | Strake M.,Helmholtz Institute for Biomedical Engineering | And 4 more authors.
RoFo Fortschritte auf dem Gebiet der Rontgenstrahlen und der Bildgebenden Verfahren | Year: 2011

Purpose: Dynamic hip screw (DHS) insertion for the fixation of lateral femoral neck fractures is an accepted surgical treatment method. A computer-assisted planning and navigation system based on 2D fluoroscopy has been developed for guidewire insertion in order to perform screw placement. The image acquisition process was supported by a radiation-saving procedure called zero-dose C-arm navigation. The aim of this study was to evaluate this new system. Materials and Methods: In the context of a sawbone study, we inserted dynamic hip screws. The procedure was performed under navigation control and in the conventional technique in 12 sawbones. Both procedures were performed in an open and closed technique. Results: The computer-assisted technique significantly reduced the number of intraoperative fluoroscopic images (open technique: -8.1 ± 0.5; p < 0.001 - closed technique: -12.3 ± 3.7; p < 0.001) and the number of guidewire passes (open technique: -1.3 ± 1.2; p < 0.05 - closed technique: -1.5 ± 1.2; p < 0,05). There was no difference with respect to precision in both groups. The operationtime was significantly longer in the navigation-assisted groups (open technique: + 14.6 ± 5.4 min; p < 0.001 - closed technique: + 13 ± 3 min; p < 0.001). Conclusion: The addition of computer-assisted planning and surgical guidance supported by zero-dose C-arm navigation may be useful for the fixation of lateral femoral neck fractures by the DHS as it reduces the amount of fluoroscopic images and requires fewer drill tracks. Further studies with the goal of reducing the operation time are necessary. © Georg Thieme Verlag KG Stuttgart - New York.


Muller M.C.,University of Bonn | Belei P.,Helmholtz Institute for Biomedical Engineering | Pennekamp P.H.,University of Bonn | Kabir K.,University of Bonn | And 3 more authors.
International Orthopaedics | Year: 2012

Purpose: Medial femoral neck fractures are common, and closed reduction and internal fixation by three cannulated screws is an accepted method for the surgical treatment. Computer navigation for screw placement may reduce fluoroscopy time, the number of guidewire passes and optimise screw placement. Methods: In the context of a sawbone study, a computerassisted planning and navigation system based on 3D-imaging for guidewire placement in the femoral neck was tested to improve screw placement. Three screws were inserted into 12, intact, femoral sawbones using the conventional technique and into 12, intact, femoral sawbones guided by the computer-based navigation system. Guidewire and subsequent screw placement in the femoral neck were evaluated. Results: Use of the navigation system resulted in a significant reduction of the number of drilling attempts (p≤0.05) and achieved optimised accuracy of implant placement by attaining significantly better screw parallelism (p≤0.05) and significantly enlarged neck-width coverage by the three screws (p≤0.0001). Computer assistance significantly increased the number of fluoroscopic images (p≤0.001) and the operation time (p≤0.0001). Conclusions: Three-dimensional computer-assisted navigation improves accuracy of cannulated screw placement in femoral neck while increasing the number of fluoroscopic images and operation time. Additional studies including fractured sawbones and cadaver models with the goal of reducing operation time are indispensable before introduction of this navigation system into clinical practice. © Springer-Verlag 2012.


Dietzel E.,Helmholtz Institute for Biomedical Engineering | Wessling J.,Helmholtz Institute for Biomedical Engineering | Floehr J.,Helmholtz Institute for Biomedical Engineering | Schafer C.,Helmholtz Institute for Biomedical Engineering | And 17 more authors.
Developmental Cell | Year: 2013

The zona pellucida (ZP) is a glycoprotein matrix surrounding mammalian oocytes. Upon fertilization, ZP hardening prevents sperm from binding to and penetrating the ZP. Here, we report that targeted gene deletion of the liver-derived plasma protein fetuin-B causes premature ZP hardening and, consequently, female infertility. Transplanting fetuin-B-deficient ovaries into wild-type recipients restores fertility, indicating that plasma fetuin-B is necessary and sufficient for fertilization. In vitro fertilization of oocytes from fetuin-B-deficient mice only worked after rendering the ZP penetrable by laser perforation. Mechanistically, fetuin-B sustains fertility by inhibiting ovastacin, a cortical granula protease known to trigger ZP hardening. Thus, plasma fetuin-B is necessary to restrain protease activity and thereby maintain ZP permeability until after gamete fusion. These results also show that premature ZP hardening can cause infertility in mice. © 2013 Elsevier Inc.


Bartneck M.,RWTH Aachen | Ritz T.,RWTH Aachen | Keul H.A.,RWTH Aachen | Wambach M.,RWTH Aachen | And 12 more authors.
ACS Nano | Year: 2012

Targeted nanomedicine holds enormous potential for advanced diagnostics and therapy. Although it is known that nanoparticles accumulate in liver in vivo, the impact of cell-targeting particles on the liver, especially in disease conditions, is largely obscure. We had previously demonstrated that peptide-conjugated nanoparticles differentially impact macrophage activation in vitro. We thus comprehensively studied the distribution of gold nanorods (AuNR) in mice in vivo and assessed their hepatotoxicity and impact on systemic and hepatic immune cells in healthy animals and experimental liver disease models. Gold nanorods were stabilized with either cetyltrimethylammonium bromide or poly(ethylene glycol) and additional bioactive tripeptides RGD or GLF. Gold nanorods mostly accumulated in liver upon systemic injection in mice, as evidenced by inductively coupled plasma mass spectrometry from different organs and by non-invasive microcomputerized tomography whole-body imaging. In liver, AuNR were only found in macrophages by seedless deposition and electron microscopy. In healthy animals, AuNR did not cause significant hepatotoxicity as evidenced by biochemical and histological analyses, even at high AuNR doses. However, flow cytometry and gene expression studies revealed that AuNR polarized hepatic macrophages, even at low doses, dependent on the respective peptide sequence, toward M1 or M2 activation. While peptide-modified AuNR did not influence liver scarring, termed fibrosis, in chronic hepatic injury models, AuNR-induced preactivation of hepatic macrophages significantly exacerbated liver damage and disease activity in experimental immune-mediated hepatitis in mice. Bioactively targeted gold nanoparticles are thus potentially harmful in clinically relevant settings of liver injury, as they can aggravate hepatitis severity. © 2012 American Chemical Society.


PubMed | Helmholtz Institute for Biomedical Engineering and RWTH Aachen
Type: Journal Article | Journal: Human reproduction (Oxford, England) | Year: 2016

Is serum fetuin-B associated with the fertilization rate in in vitro fertilization (IVF)?Serum fetuin-B increased during IVF cycles when oocytes could be fertilized while remained unchanged in fertilization failure.Fetuin-B deficiency in mice causes premature zona pellucida hardening mediated by the zona protease ovastacin. Thus fetuin-B deficiency renders females infertile.We determined the human serum fetuin-B reference range, studying longitudinally, over the course of one month, five male and seven female volunteers without hormone treatment and four female volunteers on varying hormonal contraception. We sampled blood and determined serum fetuin-B, luteinizing hormone (LH), estradiol (E2) and progesterone (P4). In addition, we determined serum fetuin-B and estradiol in eight women undergoing intracytoplasmatic sperm injection (ICSI, nine ICSI cycles) and 19 women undergoing IVF (21 IVF cycles) after ovarian stimulation with recombinant human follicular stimulating hormone (rFSH) and/or a combined medication of FSH and LH. At least three blood samples were analyzed in each cycle. We compared serum fetuin-B and follicular fluid fetuin-B in nine patients by measuring follicular fetuin-B in pooled follicular fluid, and in fluid obtained from individual follicles. Samples were drawn from January 2012 to March 2014.All volunteers and patients gave informed consent. Fetuin-B was measured employing a commercial sandwich enzyme-linked immunosorbent assay. Serum fetuin-B was determined as duplicates in 5 male (34 14.6 years) and 11 female volunteers (29.4 4.1 years) as well as in female volunteers on hormonal contraception (30.0 6.5 years). The duplicate standard deviation was 4.0 2.3%. The contraceptive drugs were mono or combined preparations containing 0-0.03 mg ethinyl estradiol, and 0.15-3.0 mg of various progestins. In addition, serum fetuin-B was determined as triplicates in 27 female patients undergoing conventional IVF (19) or ICSI (8). The triplicate standard deviation was 3.3 1.8%. IVF was declared as successful, if at least one oocyte was fertilized, and unsuccessful, if no oocyte could be fertilized. Patient age was 34.4 4.4 years in successful IVF, and 35.4 3.3 years in unsuccessful IVF. Serum and follicular fluid of patients undergoing controlled ovarian hyperstimulation were analyzed. Serum was drawn at the day of follicle aspiration.Serum fetuin-B and follicular fluid fetuin-B were not significantly different in six out of nine patients suggesting, in principle, free exchange of fetuin-B between serum and follicular fluid. Thus serum fetuin-B may be used as a proxy of follicular fluid fetuin-B. Serum fetuin-B increased during successful IVF cycles (n = 15, P < 0.0001), but did not change in unsuccessful IVF cycles (n = 6, P = 0.118) despite increased estradiol levels (P = 0.0019 and P = 0.0254, respectively).The female volunteers self-reported their respective hormone medication. Medication was verified by serum estradiol, LH and progesterone measurements. For oocyte harvesting, the vaginal wall was punctured once only to minimize co-morbidity. Low grade cross-contamination of individual follicular fluid aspirates and contamination of the follicular fluid with small amounts of blood were inevitable. Samples were routinely checked for the presence of hemoglobin that would suggest blood contamination. Only samples containing <250 erythrocyte equivalents/l were used for analysis.Serum fetuin-B may be used as a marker to predict the fertilization success in IVF. Fetuin-B levels attained during IVF stimulation may help to make an informed decision whether oocytes should be fertilized by IVF or by ICSI to overcome the zona pellucida as a barrier.The research was supported by a grant from Deutsche Forschungsgemeinschaft and by the START program of the Medical Faculty of RWTH Aachen University. J.F., E.D., J.N., B.R. and W.J.-D. declare that they are named inventors on the RWTH Aachen University patent application EP 13157317.2, Use of fetuin-B for culture of oocytes, applied for by RWTH Aachen University.


PubMed | Helmholtz Institute for Biomedical Engineering
Type: Journal Article | Journal: Aging | Year: 2011

All tissues of the organism are affected by aging. This process is associated with epigenetic modifications such as methylation changes at specific cytosine residues in the DNA (CpG sites). Here, we have identified an Epigenetic-Aging-Signature which is applicable for many tissues to predict donor age. DNA-methylation profiles of various cell types were retrieved from public data depositories - all using the HumanMethylation27 BeadChip platform which represents 27,578 CpG sites. Five datasets from dermis, epidermis, cervical smear, T-cells and monocytes were used for Pavlidis Template Matching to identify 19 CpG sites that are continuously hypermethylated upon aging (R>0.6; p-value<10-13). Four of these CpG sites (associated with the genes NPTX2, TRIM58, GRIA2 and KCNQ1DN) and an additional hypomethylated CpG site (BIRC4BP) were implemented in a model to predict donor age. This Epigenetic-Aging-Signature was tested on a validation group of eight independent datasets corresponding to several cell types from different tissues. Overall, the five CpG sites revealed age-associated DNA-methylation changes in all tissues. The average absolute difference between predicted and real chronological age was about 11 years. This method can be used to predict donor age in various cell preparations - for example in forensic analysis.

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