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  • 1
    Keywords: ENVIRONMENT ; Germany ; MODEL ; MODELS ; ALGORITHM ; INFORMATION ; EPIDEMIOLOGY ; GENE ; SAMPLE ; MARKER ; ASSOCIATION ; LINKAGE ; polymorphism ; single nucleotide polymorphism ; statistics ; smoking ; MARKERS ; REGION ; REGIONS ; LINKAGE DISEQUILIBRIUM ; HLA ; PREDICTORS ; LOCATION ; SINGLE ; REGRESSION ; RHEUMATOID-ARTHRITIS ; interaction ; analysis ; methods ; GENOTYPE ; single-nucleotide ; single-nucleotide polymorphism ; mantel statistics ; POWER ; PREDICTOR ; LINKAGE-DISEQUILIBRIUM ; SET ; ENVIRONMENTAL-FACTORS ; case control ; LOGISTIC-REGRESSION ; comparison ; case-control ; association study ; sex ; genetic analysis
    Abstract: Accounting for interactions with environmental factors in association studies may improve the power to detect genetic effects and may help identifying important environmental effect modifiers. The power of unphased genotype-versus haplotype-based methods in regions with high linkage disequilibrium (LD), as measured by D', for analyzing gene x environment (gene x sex) interactions was compared using the Genetic Analysis Workshop 15 (GAW15) simulated data on rheumatoid arthritis with prior knowledge of the answers. Stepwise and regular conditional logistic regression (CLR) was performed using a matched case-control sample for a HLA region interacting with sex. Haplotype-based analyses were performed using a haplotype-sharing-based Mantel statistic and a test for haplotype-trait association in a general linear model framework. A step-down minP algorithm was applied to derive adjusted p-values and to allow for power comparisons. These methods were also applied to the GAW15 real data set for PTPN22.For markers in strong LD, stepwise CLR performed poorly because of the correlation/collinearity between the predictors in the model. The power was high for detecting genetic main effects using simple CLR models and haplotype-based methods and for detecting joint effects using CLR and Mantel statistics. Only the haplotype-trait association test had high power to detect the gene x sex interaction.In the PTPN22 region with markers characterized by strong LD, all methods indicated a significant genotype x sex interaction in a sample of about 1000 subjects. The previously reported R620W single-nucleotide polymorphism was identified using logistic regression, but the haplotype-based methods did not provide any precise location information.
    Type of Publication: Journal article published
    PubMed ID: 18466575
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR); 20140917-20140920; Düsseldorf; DOCRA.38 /20140912/
    Publication Date: 2014-09-13
    Keywords: Treatment Patterns ; Rheumatoid Arthritis ; Germany ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
    Keywords: CELL ; Germany ; MICROSCOPY ; imaging ; SAMPLES ; RESOLUTION ; MARKER ; MARKERS ; ENDOPLASMIC-RETICULUM ; methods ; STIMULATED-EMISSION ; DEPLETION ; subdiffraction ; FLUORESCENT PROTEIN
    Abstract: We report attainment of subdiffraction resolution using stimulated emission depletion (STED) microscopy with GFP-labeled samples. The similar to 70 nm lateral resolution attained in this study is demonstrated by imaging GFP-labeled viruses and the endoplasmic reticulum (ER) of a mammalian cell. Our results mark the advent of nanoscale biological microscopy with genetically encoded markers
    Type of Publication: Journal article published
    PubMed ID: 16896340
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  • 4
    Keywords: IN-VITRO ; carcinoma ; evaluation ; Germany ; human ; LUNG ; MODEL ; MODELS ; PERFUSION ; VITRO ; imaging ; SYSTEM ; SYSTEMS ; TOOL ; liver ; SURGERY ; NUCLEAR-MEDICINE ; ASSOCIATION ; NO ; metastases ; RADIOFREQUENCY ABLATION ; HUMAN LIVER ; MOTION ; TRACKING ; BODY ; ESTABLISHMENT ; DEFORMATION ; nuclear medicine ; COMPLICATIONS ; BIOPSY ; MANAGEMENT ; radiology ; BODIES ; MOVEMENT ; development ; DIAPHRAGM ; NUCLEAR ; TESTS ; USA ; TOOLS ; RESPIRATORY MOTION ; phantom ; physics ; THERMAL ABLATION ; navigation ; MEDICINE ; respiratory liver motion simulator ; abdominal procedures ; HEPATIC-TUMORS ; image-guided therapy ; liver deformation
    Abstract: Image-guided surgery and navigation have resulted from convergent developments in radiology, teletransmission, and computer science and are well-established procedures in the surgical routine in orthopedic, neurosurgery, and head-and-neck surgery. In abdominal surgery, however, these tools have gained little attraction so far. The inability to transfer the methodology from orthopedic or neurosurgery is mainly a result of intraoperative organ movement and shifting. To practice and establish navigated interventions in the liver, a custom-designed respiratory liver motion simulator was built which models the human torso and is easy to recreate. To simulate breathing motion, an explanted porcine or human liver is mounted to the diaphragm model of the simulator, and a lung ventilator causes a periodic movement of the liver along the craniocaudal axis. Additionally, the liver can be connected to a circulating pump device which simulates hepatic perfusion and provides real surgical options to establish navigated interventions and simulate management of possible complications. Respiratory motion caused by the simulator was evaluated with an optical tracking system and it was shown that in vitro movement and deformation of a liver mounted to the device are similar to the liver movements in human or porcine bodies. Based on the tests, it is concluded that the novel respiratory liver motion simulator is suitable for in vitro evaluation of navigated systems and interventional and surgical procedures. (C) 2007 American Association of Physicists in Medicine
    Type of Publication: Journal article published
    PubMed ID: 18196787
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  • 5
    Keywords: Germany ; ALGORITHM ; DISEASE ; DISEASES ; EXPOSURE ; GENE ; GENES ; SAMPLE ; MARKER ; ASSOCIATION ; VARIANTS ; HEALTH ; genetics ; MARKERS ; LINKAGE DISEQUILIBRIUM ; gene-environment interaction ; PREVALENCE ; heredity ; case-control study ; RE ; VARIANT ; interaction ; analysis ; POWER ; TECHNOLOGY ; USA ; VARIABLES ; genetic association ; association study ; interactions ; DETECT ; GENE-ENVIRONMENT INTERACTIONS ; indirect association ; gene-environment interaction effect
    Abstract: Association studies accounting for gene-environment interactions (G x E) may be useful for detecting genetic effects. Although current technology enables very dense marker spacing in genetic association studies, the true disease variants may not be genotyped. Thus, causal genes are searched for by indirect association using genetic markers in linkage disequilibrium (LD) with the true disease variants. Sample sizes needed to detect G x E effects in indirect case-control association studies depend on the true genetic main effects, disease allele frequencies, whether marker and disease allele frequencies match, LD between loci, main effects and prevalence of environmental exposures, and the magnitude of interactions. We explored variables influencing sample sizes needed to detect G x E, compared these sample sizes with those required to detect genetic marginal effects, and provide an algorithm for power and sample size estimations. Required sample sizes may be heavily, inflated if LD between marker and disease loci decreases. More than 10,000 case-control pairs may be required to detect G x E. However, given weak true genetic main effects, moderate prevalence of environmental exposures, as well as strong interactions, G x E effects may be detected with smaller sample sizes than those needed for the detection of genetic marginal effects. Moreover, in this scenario, rare disease variants may only be detectable when G x E is included in the analyses. Thus, the analysis of G x E appears to be an attractive option for the detection of weak genetic main effects of rare variants that may not be detectable in the analysis of genetic marginal effects only
    Type of Publication: Journal article published
    PubMed ID: 18163529
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  • 6
    Keywords: OPTIMIZATION ; tumor ; Germany ; IN-VIVO ; VIVO ; CT ; imaging ; SUPPORT ; SYSTEM ; liver ; TUMORS ; ACCURACY ; computed tomography ; NUCLEAR-MEDICINE ; TIME ; TARGET ; NO ; TRIAL ; TRIALS ; ACQUISITION ; LESIONS ; EXPERIENCE ; RADIOFREQUENCY ABLATION ; REGISTRATION ; tomography ; COMPUTED-TOMOGRAPHY ; MOTION ; TRACKING ; IMAGE REGISTRATION ; nuclear medicine ; ORGAN MOTION ; radiology ; RE ; GUIDANCE ; ABLATION ; radiation therapy ; NUCLEAR ; USA ; SET ; IMPROVEMENT ; navigation ; MEDICINE ; CHALLENGES ; INSERTION ; HEPATIC-TUMORS ; INTERVENTIONS ; tumours ; NEEDLES ; computerised tomography ; needle insertion ; CLINICAL-EVALUATION ; motion compensation ; patient treatment
    Abstract: Computed tomography (CT)-guided percutaneous radiofrequency ablation (RFA) has become a commonly used procedure in the treatment of liver tumors. One of the main challenges related to the method is the exact placement of the instrument within the lesion. To address this issue, a system was developed for computer-assisted needle placement which uses a set of fiducial needles to compensate for organ motion in real time. The purpose of this study was to assess the accuracy of the system in vivo. Two medical experts with experience in CT-guided interventions and two nonexperts used the navigation system to perform 32 needle insertions into contrasted agar nodules injected into the livers of two ventilated swine. Skin-to-target path planning and real-time needle guidance were based on preinterventional 1 mm CT data slices. The lesions were hit in 97% of all trials with a mean user error of 2.4 +/- 2.1 mm, a mean target registration error (TRE) of 2.1 +/- 1.1 mm, and a mean overall targeting error of 3.7 +/- 2.3 mm. The nonexperts achieved significantly better results than the experts with an overall error of 2.8 +/- 1.4 mm (n=16) compared to 4.5 +/- 2.7 mm (n=16). The mean time for performing four needle insertions based on one preinterventional planning CT was 57 +/- 19 min with a mean setup time of 27 min, which includes the steps fiducial insertion (24 +/- 15 min), planning CT acquisition (1 +/- 0 min), and registration (2 +/- 1 min). The mean time for path planning and targeting was 5 +/- 4 and 2 +/- 1 min, respectively. Apart from the fiducial insertion step, experts and nonexperts performed comparably fast. It is concluded that the system allows for accurate needle placement into hepatic tumors based on one planning CT and could thus enable considerable improvement to the clinical treatment standard for RFA procedures and other CT-guided interventions in the liver. To support clinical application of the method, optimization of individual system modules to reduce intervention time is proposed
    Type of Publication: Journal article published
    PubMed ID: 19175098
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  • 7
    Keywords: RECEPTOR ; EXPRESSION ; CELL ; Germany ; IN-VIVO ; LUNG ; VIVO ; DENSITY ; SYSTEM ; SYSTEMS ; GENE ; PROTEIN ; HEART ; MICE ; MOUSE ; MUTANT ; NO ; genetics ; WILD-TYPE ; arteries ; LOCALIZATION ; TRACT ; ARTERY ; BODY ; FAILURE ; RECEPTORS ; VESSELS ; SMOOTH-MUSCLE ; LACKING ; HYPOXIA ; signaling ; PULMONARY ; BODIES ; TARGETED DISRUPTION ; hypertension,pulmonary ; CYCLASE ; catheterization ; heart failure ; HEART-FAILURE ; HUMAN LUNG ; NEUROENDOCRINE ; PACAP ; VASOACTIVE-INTESTINAL-PEPTIDE ; VIP
    Abstract: Background - Pituitary adenylate cyclase - activating polypeptide (PACAP), acting via 3 different G protein - coupled receptors, has been implicated in the regulation of several homeostatic systems in the body, including cardiopulmonary control. To define the physiologic role of the PACAP-preferring type I receptor, PAC1, in cardiopulmonary function, we developed a mutant mouse strain lacking functional PAC1 receptors. Methods and Results - When PAC1-deficient mice were crossed onto a C57BL/6 background, almost all mutants died during the second postnatal week. Whereas mutant mice were indistinguishable from their wild-type littermates at birth, they showed progressive weakness and died from rapidly developing heart failure. Right ventricles of PAC1 mutants were massively dilated and showed cardiac myocyte hypertrophy, whereas left ventricular structure was unaltered. On direct cardiac catheterization, right ventricular pressure was elevated by 45% in PAC1-deficient mice, indicating increased pulmonary artery pressure, as no malformations were detected in the valves or outflow tract of the right ventricle. Consistent with elevated pulmonary pressure, lung capillary density was decreased by 30% and small pulmonary arteries of mutant mice had significant vascular smooth muscle cell hypertrophy compared with wild-type mice. Conclusions - Whereas PACAP induces vasodilation in isolated pulmonary vessels in wild-type mice, the absence of its specific receptor PAC1 causes pulmonary hypertension and right heart failure after birth. These in vivo findings demonstrate the crucial importance of PAC1-mediated signaling for the maintenance of normal pulmonary vascular tone during early postnatal life
    Type of Publication: Journal article published
    PubMed ID: 15520307
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  • 8
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  42. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 28. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 24. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR); 20140917-20140920; Düsseldorf; DOCRA.37 /20140912/
    Publication Date: 2014-09-13
    Keywords: Resource Use ; Associated Costs ; Rheumatoid Arthritis ; Germany ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 9
    Keywords: Germany ; human ; DISEASE ; DISEASES ; EPIDEMIOLOGY ; RISK ; GENE ; GENES ; SAMPLE ; COMPLEX ; RISK-FACTORS ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; STAGE ; DESIGN ; DIFFERENCE ; CLINICAL-TRIALS ; genetics ; risk factors ; gene-environment interaction ; LIFE-STYLE ; heredity ; molecular biology ; molecular ; review ; CANDIDATE GENES ; interaction ; PHARMACOGENETICS ; analysis ; GENOTYPE ; POWER ; INFECTIOUS-DISEASES ; RISK-FACTOR ; ENGLAND ; CHALLENGES ; genetic association ; interactions ; CLINICAL-PRACTICE ; disease genes ; effect modification ; GENE-ENVIRONMENT INTERACTIONS ; PHARMACOGENETIC TRIALS ; SAMPLE-SIZE REQUIREMENTS
    Abstract: Genetic and environmental risk factors and their interactions contribute to the development of complex diseases. In this review, we discuss methodological issues involved in investigating gene-environment (G x E) interactions in genetic-epidemiological studies of complex diseases and their potential relevance for clinical application. Although there are some important examples of interactions and applications, the widespread use of the knowledge about G x E interaction for targeted intervention or personalized treatment (pharmacogenetics) is still beyond current means. This is due to the fact that convincing evidence and high predictive or discriminative power are necessary conditions for usefulness in clinical practice. We attempt to clarify conceptual differences of the term 'interaction' in the statistical and biological sciences, since precise definitions are important for the interpretation of results. We argue that the investigation of G x E interactions is more rewarding for the detailed characterization of identified disease genes (ie at advanced stages of genetic research) and the stratified analysis of environmental effects by genotype or vice versa. Advantages and disadvantages of different epidemiological study designs are given and sample size requirements are exemplified. These issues as well as a critical appraisal of common methodological concerns are finally discussed
    Type of Publication: Journal article published
    PubMed ID: 18523454
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  • 10
    Keywords: IN-VITRO ; tumor ; Germany ; human ; MODEL ; THERAPY ; VITRO ; CT ; SYSTEM ; liver ; ACCURACY ; computed tomography ; SURGERY ; TARGET ; REGISTRATION ; STRATEGIES ; COMPUTED-TOMOGRAPHY ; MOTION ; TRACKING ; BIOPSY ; RE ; THERAPIES ; ABLATION ; THIN-PLATE SPLINES ; RESPIRATORY MOTION ; ENGLAND ; THERMAL ABLATION ; navigation ; respiratory liver motion simulator ; POSITION ; INTERVENTIONS ; NEEDLES ; DEVICE ; deformation model ; image-guided systems ; interventional radiology ; needle insertion ; respiratory motion compensation
    Abstract: Computed tomography (CT) guided minimally invasive procedures in the liver, such as tumor biopsy and thermal ablation therapy, require precise targeting of hepatic structures that are subject to breathing motion. To facilitate needle placement, we introduced a navigation system which uses needle-shaped optically tracked navigation aids and a real-time deformation model to continuously estimate the position of a moving target. In this study, we assessed the target position estimation accuracy of our system in vitro with a custom-designed respiratory liver motion simulator. Several real-time compatible transformations were compared as a basis for the deformation model and were evaluated in a set of experiments using different arrangements of three navigation aids in two porcine and two human livers. Furthermore, we investigated different placement strategies for the case where only two needles are used for motion compensation. Depending on the transformation and the placement of the navigation aids, our system yielded a root mean square (RMS) target position estimation error in the range of 0.7 mm to 2.9 mm throughout the breathing cycle generated by the motion simulator. Affine transformations and spline transformations performed comparably well (overall RMS 〈 2 mm) and were considerably better than rigid transformations. When two navigation aids were used for motion compensation instead of three, a diagonal arrangement of the needles yielded the best results. This study suggests that our navigation system could significantly improve the clinical treatment standard for CT-guided interventions in the liver
    Type of Publication: Journal article published
    PubMed ID: 18432412
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