22 results on '"Igl BW"'
Search Results
2. A multivariate Bayesian approach for incorporating historical data into the assessment of test items in reproductive toxicology
- Author
-
Sandig, L, Baier, B, Ickstadt, K, Igl, BW, Sandig, L, Baier, B, Ickstadt, K, and Igl, BW
- Published
- 2021
3. Endpoints of drug discovery for menopausal vasomotor symptoms: interpretation of data from a proxy of disease.
- Author
-
Prelle K, Igl BW, Obendorf M, Girbig D, Lehmann T, Patchev VK, Prelle, Katja, Igl, Bernd-Wolfgang, Obendorf, Maik, Girbig, Dorothee, Lehmann, Tanja, and Patchev, Vladimir K
- Published
- 2012
- Full Text
- View/download PDF
4. A Minimal Approach to Demonstrate Concordance of Digital and Conventional Microscopy in Toxicologic Pathology.
- Author
-
Lempp C, Arms S, Bertram CA, Klopfleisch R, Igl BW, Hezler L, Nolte T, and Pohlmeyer-Esch G
- Subjects
- Animals, Image Processing, Computer-Assisted methods, Humans, Microscopy methods, Pathology methods, Pathology standards, Toxicology methods, Toxicology standards
- Abstract
Digitalization of pathology workflows has undergone a rapid evolution and has been widely established in the diagnostic field but remains a challenge in the nonclinical safety context due to lack of regulatory guidance and validation experience for good laboratory practice (GLP) use. One means to demonstrate that digital slides are fit for purpose, that is, provide sufficient quality for pathologists to reach a diagnosis, is conduction of comparison studies, which have been published both, for veterinary and human diagnostic pathology, but not for toxicologic pathology. Here, we present an approach that uses study material from nonclinical safety studies and that allows for the statistical comparison of concordance rates for glass and digital slide evaluation while minimizing time and effort for the involved personnel. Using a benchmark study design, we demonstrate that evaluation of digital slides fits the purpose of nonclinical safety evaluation. These results add to reports of successful workflow validations and support the full adaptation of digital pathology in the regulatory field., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CL, SA, B-WI, LH, TN, and GP-E are employed by Boehringer Ingelheim Pharma GmbH & Co. KG. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
- Full Text
- View/download PDF
5. In vivo alkaline comet assay: Statistical considerations on historical negative and positive control data.
- Author
-
Tug T, Duda JC, Menssen M, Bruce SW, Bringezu F, Dammann M, Frötschl R, Harm V, Ickstadt K, Igl BW, Jarzombek M, Kellner R, Lott J, Pfuhler S, Plappert-Helbig U, Rahnenführer J, Schulz M, Vaas L, Vasquez M, Ziegler V, and Ziemann C
- Subjects
- Animals, Comet Assay methods, Reproducibility of Results, Mutation, DNA Damage, Research Design
- Abstract
The alkaline comet assay is frequently used as in vivo follow-up test within different regulatory environments to characterize the DNA-damaging potential of different test items. The corresponding OECD Test guideline 489 highlights the importance of statistical analyses and historical control data (HCD) but does not provide detailed procedures. Therefore, the working group "Statistics" of the German-speaking Society for Environmental Mutation Research (GUM) collected HCD from five laboratories and >200 comet assay studies and performed several statistical analyses. Key results included that (I) observed large inter-laboratory effects argue against the use of absolute quality thresholds, (II) > 50% zero values on a slide are considered problematic, due to their influence on slide or animal summary statistics, (III) the type of summarizing measure for single-cell data (e.g., median, arithmetic and geometric mean) may lead to extreme differences in resulting animal tail intensities and study outcome in the HCD. These summarizing values increase the reliability of analysis results by better meeting statistical model assumptions, but at the cost of information loss. Furthermore, the relation between negative and positive control groups in the data set was always satisfactorily (or sufficiently) based on ratio, difference and quantile analyses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
6. Statistical analysis of in vivo alkaline comet assay data - Comparison of median and geometric mean as centrality measures.
- Author
-
Tug T, Ickstadt K, Kunz M, Sutter A, and Igl BW
- Subjects
- Animals, Computer Simulation, Data Interpretation, Statistical, Liver pathology, Models, Statistical, Rats, Risk Assessment, Comet Assay statistics & numerical data, DNA Damage, Liver drug effects
- Abstract
The comet assay is one of the standard tests for evaluating the genotoxic potential of a test item able to detect DNA strand breaks in cells or isolated nuclei from various tissues. The in vivo alkaline comet assay is part of the standard test battery, given in option 2 of the ICH guidance S2 (R1) and a follow-up test in the EFSA framework on genotoxicity testing. The current OECD guideline for the testing of chemicals No. 489 directly affects the statistical analysis of comet data as it suggests using the median per slide and the mean of all medians per animal. However, alternative approaches can be used if scientifically justified. In this work, we demonstrated that the selection of different centrality measures to describe an average value per slide may lead to fundamentally different statistical test results and contradicting interpretations. Our focus was on geometric means and medians per slide for the primary endpoint "tail intensity". We compared both strategies using original and simulated data in different experimental settings incl. a varying number of animals, slides and cells per slide. In general, it turned out that the chosen centrality measure has an immense impact on the final statistical test result., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
7. Evaluation of high-sensitivity C-reactive protein and uric acid in vericiguat-treated patients with heart failure with reduced ejection fraction.
- Author
-
Kramer F, Voss S, Roessig L, Igl BW, Butler J, Lam CSP, Maggioni AP, Shah SJ, and Pieske B
- Subjects
- Aged, C-Reactive Protein, Female, Heterocyclic Compounds, 2-Ring, Humans, Male, Middle Aged, Pyrimidines, Stroke Volume, Uric Acid, Ventricular Function, Left, Heart Failure drug therapy
- Abstract
Aims: The effects of vericiguat vs. placebo on high-sensitivity C-reactive protein (hsCRP) and serum uric acid (SUA) were assessed in patients with heart failure with reduced ejection fraction (HFrEF) in the Phase 2 SOCRATES-REDUCED study (NCT01951625)., Methods and Results: Changes from baseline hsCRP and SUA values at 12 weeks with placebo and vericiguat (1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg, respectively) were assessed. The probability of achieving an hsCRP value of ≤3.0 mg/L or SUA value of <7.0 mg/dL at week 12 was tested. Median baseline hsCRP and SUA levels were 3.68 mg/L [interquartile range (IQR) 1.41-8.41; n = 335] and 7.80 mg/dL (IQR 6.40-9.33; n = 348), respectively. Baseline-adjusted mean percentage changes in hsCRP were 0.2%, -19.5%, -24.3%, -25.7% and -31.9% in the placebo and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the vericiguat 10.0 mg group (P = 0.035). Baseline-adjusted mean percentage changes in SUA were 5.0%, -1.3%, -1.1%, -3.5% and -5.3% in the placebo, and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the 5.0 mg and 10.0 mg groups (P = 0.0202 and P = 0.004, respectively). Estimated probability for an end-of-treatment hsCRP value of ≤3.0 mg/L and SUA value of <7.0 mg/dL was higher with vericiguat compared with placebo. The effect was dose-dependent, with the greatest effect observed in the 10.0 mg group., Conclusions: Vericiguat treatment for 12 weeks was associated with reductions in hsCRP and SUA, and a higher likelihood of achieving an hsCRP value of ≤3.0 mg/L and SUA value of <7.0 mg/dL., (© 2020 Bayer AG Pharmaceuticals. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
- Published
- 2020
- Full Text
- View/download PDF
8. The rat bone marrow micronucleus test: Statistical considerations on historical negative control data.
- Author
-
Igl BW, Bitsch A, Bringezu F, Chang S, Dammann M, Frötschl R, Harm V, Kellner R, Krzykalla V, Lott J, Nern M, Pfuhler S, Queisser N, Schulz M, Sutter A, Vaas L, Vonk R, Zellner D, and Ziemann C
- Subjects
- Animals, Bone Marrow, Female, Male, Rats, Wistar, Reference Values, Control Groups, Micronucleus Tests statistics & numerical data
- Abstract
Recent updates of the OECD Guidelines for the Testing of Chemicals (Section 4: Health Effects) on genotoxicity testing emphasize the use of appropriate statistical methods for data analysis and proficiency proof. Updates also concern the mammalian erythrocyte micronucleus test (OECD 474), as the currently most often performed regulatory in vivo test. As the updated guideline gives high importance to adequate statistical assessment of historical negative control data to estimate validity of experiments and judge results, the present study evaluated statistical methodologies for handling of historical negative control data sets, and comes forward with respective proposals and reference data. Therefore, the working group "Statistics" within the German-speaking "Gesellschaft für Umwelt-Mutationsforschung e.V." (GUM) compiled a data set of 891 negative control rats from valid OECD 474-studies of four laboratories. Based on these data, Analysis-of-Variance (ANOVA) identified "laboratory" and "strain", but not "gender" as relevant stratification parameters, and argued for approximately normally distributed micronucleus frequencies in polychromatic erythrocytes per animal. This assumption provided the basis for further specifying one-sided parametric tolerance intervals for determination of corresponding upper historical negative control limits. Finally, the stability of such limits was investigated as a function of the number of experiments performed, using a simulation-based statistical strategy., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
9. A statistical approach for analyzing data from the in vivo Pig-a gene mutation assay.
- Author
-
Igl BW, Dertinger SD, Dobrovolsky VN, Raschke M, Sutter A, and Vonk R
- Subjects
- Animals, Antineoplastic Agents, Alkylating toxicity, Biological Assay, DNA Damage, Erythrocytes drug effects, Erythrocytes metabolism, Male, Membrane Proteins blood, Models, Statistical, Mutagenicity Tests, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Chlorambucil toxicity, Erythrocytes pathology, Gene Expression Regulation drug effects, Membrane Proteins genetics, Micronucleus Tests methods, Mutation
- Abstract
The in vivo Pig-a gene mutation assay serves to evaluate the genotoxic potential of chemicals. In the rat blood-based assay, the lack of CD59 on the surface of erythrocytes is quantified via fluorophore-labeled antibodies in conjunction with flow cytometric analysis to determine the frequency of Pig-a mutant phenotype cells. The assay has achieved regulatory relevance as it is suggested as an in vivo follow-up test for Ames mutagens in the recent ICH M7 [25] step 4 document. However, very little work exists regarding suitable statistical approaches for analyzing Pig-a data. In the current report, we present a statistical strategy based on a two factor model involving 'treatment' and 'time' incl. their interaction and a baseline covariate for log proportions to compare treatment and vehicle data per time point as well as in time. In doing so, multiple contrast tests allow us to discover time-related changes within and between treatment groups in addition to multiple treatment comparisons to a control group per single time point. We compare our proposed strategy with the results of classical Dunnett and Wilcoxon-Mann-Whitney tests using two data sets describing the mode of action of Chlorambucil and Glycidyl methacrylate both analyzed in a 28-day treatment schedule., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
10. In Vivo Pig-a gene mutation assay: Guidance for 3Rs-friendly implementation.
- Author
-
Raschke M, Igl BW, Kenny J, Collins J, Dertinger SD, Labash C, Bhalli JA, Tebbe CC, McNeil KM, and Sutter A
- Subjects
- Animal Welfare, Animals, CD59 Antigens analysis, Erythrocytes drug effects, Erythrocytes metabolism, Flow Cytometry, Guidelines as Topic, Laboratories standards, Male, Rats, Inbred Strains, Reticulocytes drug effects, Reticulocytes metabolism, Animal Use Alternatives, Ethylnitrosourea toxicity, Membrane Proteins genetics, Mutagenicity Tests methods, Mutagens toxicity, Mutation
- Abstract
The rodent Pig-a assay is an in vivo method for the detection of gene mutation, where lack of glycosylphosphatidylinositol-anchored proteins on the surface of circulating red blood cells (RBCs) serves as a reporter for Pig-a gene mutation. In the case of rats, the frequency of mutant phenotype RBCs is measured via fluorescent anti-CD59 antibodies and flow cytometry. The Pig-a assay meets the growing expectations for novel approaches in animal experimentation not only focusing on the scientific value of the assay but also on animal welfare aspects (3Rs principles), for example, amenable to integration into pivotal rodent 28-day general toxicology studies. However, as recommended in the Organisation for Economic Co-operation and Development Test Guidelines for genotoxicity testing, laboratories are expected to demonstrate their proficiency. While this has historically involved the extensive use of animals, here we describe an alternative approach based on a series of blood dilutions covering a range of mutant frequencies. The experiments described herein utilized either non-fluorescent anti-CD59 antibodies to provide elevated numbers of mutant-like cells, or a low volume blood sample from a single N-ethyl-N-nitrosourea treated animal. Results from these so-called reconstruction experiments from four independent laboratories showed good overall precision (correlation coefficients: 0.9979-0.9999) and accuracy (estimated slope: 0.71-1.09) of mutant cell scoring, which was further confirmed by Bland-Altman analysis. These data strongly support the use of reconstruction experiments for training purposes and demonstrating laboratory proficiency with very few animals, an ideal situation given the typically conflicting goals of demonstrating laboratory proficiency and reducing the use of animals. Environ. Mol. Mutagen. 57:678-686, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
11. ECG telemetry in conscious guinea pigs.
- Author
-
Ruppert S, Vormberge T, Igl BW, and Hoffmann M
- Subjects
- Adrenergic beta-Antagonists pharmacology, Animals, Anti-Arrhythmia Agents pharmacology, Calcium Channel Blockers pharmacology, Dogs, Drug Evaluation, Preclinical methods, Electrodes, Implanted, Electrophysiological Phenomena drug effects, Female, Guinea Pigs, Heart drug effects, Heart Rate drug effects, Long QT Syndrome chemically induced, Long QT Syndrome physiopathology, Potassium Channel Blockers pharmacology, Reproducibility of Results, Electrocardiography instrumentation, Electrocardiography methods, Telemetry instrumentation, Telemetry methods
- Abstract
Introduction: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required., Methods: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs., Results and Conclusion: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to β-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
12. A dynamic model of circadian rhythms in rodent tail skin temperature for comparison of drug effects.
- Author
-
Girbig D, Keller K, Prelle K, Patchev V, Vonk R, and Igl BW
- Abstract
Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot flushes severely impairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat model providing time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingredient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with the aim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well-interpretable model parameters. Results regarding the statistical evaluation of these parameters are presented.
- Published
- 2012
- Full Text
- View/download PDF
13. HDAC2 and TXNL1 distinguish aneuploid from diploid colorectal cancers.
- Author
-
Gemoll T, Roblick UJ, Szymczak S, Braunschweig T, Becker S, Igl BW, Bruch HP, Ziegler A, Hellman U, Difilippantonio MJ, Ried T, Jörnvall H, Auer G, and Habermann JK
- Subjects
- Blotting, Western, CapZ Actin Capping Protein genetics, CapZ Actin Capping Protein metabolism, CapZ Actin Capping Protein physiology, Carcinoma diagnosis, Carcinoma pathology, Cell Line, Tumor, Cohort Studies, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology, DNA, Neoplasm chemistry, Genomic Instability, Histone Deacetylase 2 metabolism, Histone Deacetylase 2 physiology, Humans, Prognosis, Thioredoxins metabolism, Thioredoxins physiology, Aneuploidy, Carcinoma genetics, Colorectal Neoplasms genetics, Diploidy, Histone Deacetylase 2 genetics, Thioredoxins genetics
- Abstract
DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel-electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n=19), diploid (n=31), and aneuploid (n=47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers., (© Springer Basel AG 2011)
- Published
- 2011
- Full Text
- View/download PDF
14. High Frequency of Aneuploidy Defines Ulcerative Colitis-Associated Carcinomas: A Prognostic Comparison to Sporadic Colorectal Carcinomas.
- Author
-
Gerling M, Meyer KF, Fuchs K, Igl BW, Fritzsche B, Ziegler A, Bader F, Kujath P, Schimmelpenning H, Bruch HP, Roblick UJ, and Habermann JK
- Subjects
- Aged, Aneuploidy, Colorectal Neoplasms etiology, Colorectal Neoplasms pathology, DNA, Neoplasm genetics, Female, Humans, Male, Middle Aged, Prognosis, Colitis, Ulcerative complications, Colorectal Neoplasms genetics
- Abstract
Objective: Aneuploidy is an independent risk factor for forthcoming carcinogenesis in ulcerative colitis (UC). An inferior prognosis of patients with ulcerative colitis-associated colorectal cancer (UCC) compared with those with sporadic colorectal cancer (SCC) has been reported, but remains controversial. This prompted us to investigate if aneuploidy can be observed in UCCs as frequently as in their sporadic counterpart and if aneuploidy per se might be a driving feature of poor prognosis in UCC., Background Data: We obtained clinical follow-up for 257 SCC patients (average observation time 57 months) and 31 UCC patients (51 months). Touch preparation slides or tissue sections were prepared of all 288 carcinomas for ploidy analysis., Methods: Ploidy status was assessed for 260 SCCs and 31 UCCs by image cytometry and correlated to clinical features. Survival data were analyzed using Kaplan-Meier estimates., Results: Aneuploidy was detected in 74.6% of SCCs and in all 31 UCCs. Logistic regression analysis yielded age (odds ratio [OR], 1.05; 95% CI, 1.02-1.09; P = 0.003) and aneuploidy (OR, 4.07; 95% CI, 1.46-11.36; P = 0.007) as independent prognostic factors for R0-resected patients devoid of metastases. Diploid SCCs had a more favorable 5-year survival (88.2%) than aneuploid SCCs (69.0%) and UCCs (73.1%) (P = 0.074)., Conclusions: UC-associated carcinomas presented aneuploidy at significantly higher frequency than sporadic colorectal carcinomas (P < 0.0006). UCCs and aneuploid SCCs share a similar prognosis inferior to that of diploid SCCs. Aneuploidy proved to be the strongest independent prognostic marker for R0-resected colorectal cancer patients overall.
- Published
- 2010
- Full Text
- View/download PDF
15. Detecting SNP-expression associations: a comparison of mutual information and median test with standard statistical approaches.
- Author
-
Szymczak S, Igl BW, and Ziegler A
- Subjects
- Computer Simulation, Coronary Artery Disease genetics, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Humans, Monte Carlo Method, Gene Expression Profiling methods, Genome-Wide Association Study methods, Models, Genetic, Models, Statistical, Polymorphism, Single Nucleotide genetics
- Abstract
Single nucleotide polymorphism-gene expression associations have received increasing interest. The aim of these studies is discovering a difference in the location parameters of gene expressions given genotype. Because gene expressions often are highly skewed, heavy-tailed or data of different genotypes vary in dispersion, the median is the most appropriate measure of location. In this case, model assumptions of standard statistical methods for comparing locations such as the analysis of variance (ANOVA) or the Kruskal-Wallis (KW) test are violated. Alternatives that might be more appropriate are the median test (MED) and tests based on mutual information (MI). In simulation studies these approaches and a novel MI test are compared with ANOVA and KW. Location, dispersion and skewness parameters of the gene expression distributions given genotypes are varied as well as genotype frequencies. The MED test and the novel MI-based method keep the nominal significance levels for comparing medians if gene expression data are non-normally distributed. ANOVA and KW have substantially inflated type I errors. They are, however, optimal if standard model assumptions are fulfilled. The MED test generally has larger power than MI and is therefore recommended if model assumptions of standard procedures are violated. A 300 kb region on chromosome 9p21.3, which is associated with coronary artery disease, was analyzed using the HapMap data. Only the alternative approaches were able to identify three genes (ADM, FCGR3B and ADORA1) as promising candidates to clarify the molecular mechanism of the genetic association.
- Published
- 2009
- Full Text
- View/download PDF
16. Blood gas partition coefficient and pulmonary extraction ratio for propofol in goats and pigs.
- Author
-
Grossherr M, Hengstenberg A, Dibbelt L, Igl BW, Noel R, Knesebeck Av, Schmucker P, and Gehring H
- Subjects
- Anesthetics, Intravenous blood, Animals, Blood Gas Analysis, Exhalation, Goats, Propofol blood, Swine, Anesthetics, Intravenous analysis, Lung metabolism, Propofol analysis
- Abstract
The interpretation of continuously measured propofol concentration in respiratory gas demands knowledge about the blood gas partition coefficient and pulmonary extraction ratio for propofol. In the present investigation we compared both variables for propofol between goats and pigs during a propofol anaesthesia. In ten goats and ten pigs, expired alveolar gas and arterial and mixed venous blood samples were simultaneously drawn during total intravenous anaesthesia with propofol. The blood gas partition coefficient and pulmonary extraction ratio were calculated for both species. Non-parametric methods were used for statistical inference. The blood gas partition coefficient ranged between 7000 and 646,000 for goats and between 17,000 and 267,000 for pigs. The pulmonary extraction ratio ranged between 32.9% and 98.1% for goats and was higher for pigs, which ranged between -106.0% and 39.0%. The blood gas partition coefficient for propofol exceeded those for other known anaesthetic compounds so that it takes longer to develop a steady-state. The different pulmonary extraction rates in two species suggest that there are different ways to distribute propofol during the lung passage on its way from the blood to breathing gas. This species-specific difference has to be considered for methods using the alveolar gas for monitoring the propofol concentration in plasma.
- Published
- 2009
- Full Text
- View/download PDF
17. Autoantibodies against epidermal transglutaminase are a sensitive diagnostic marker in patients with dermatitis herpetiformis on a normal or gluten-free diet.
- Author
-
Rose C, Armbruster FP, Ruppert J, Igl BW, Zillikens D, and Shimanovich I
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Autoantigens immunology, Celiac Disease immunology, Diet, Gluten-Free, Epidermis enzymology, Female, Humans, Male, Middle Aged, Autoantibodies blood, Celiac Disease diagnosis, Dermatitis Herpetiformis diagnosis, Dermatitis Herpetiformis immunology, Immunoglobulin A blood, Transglutaminases immunology
- Abstract
Background: Dermatitis herpetiformis (DH) is a cutaneous manifestation of gluten-sensitive enteropathy (celiac disease). Patients with DH demonstrate circulating IgA antibodies against epidermal transglutaminase (eTG) and tissue transglutaminase (tTG). It has been suggested that eTG is the autoantigen of DH., Objective: The purpose of this study was to characterize the autoimmune response to eTG and tTG in patients with DH on a normal or gluten-free diet (GFD)., Methods: Sera from 52 patients with DH were studied for the presence of IgA antibodies to eTG and tTG by enzyme-linked immunosorbant assay. In 38 patients, serum was obtained before initiation of a GFD, whereas 14 patients had been on a GFD for at least 2 years., Results: Autoantibodies against eTG were detected in 36 of 38 patients (95%) and those against tTG in 30 of 38 patients (79%) with DH on a normal diet. Of 14 patients on a long-term GFD, 7 patients were free of DH lesions and did not require dapsone treatment. None of these patients showed circulating antibodies against eTG or tTG. The remaining 7 patients on a GFD were not able to stop taking dapsone. All these patients demonstrated anti-eTG antibodies, whereas only 3 of them showed additional reactivity against tTG., Limitation: Autoantibody levels against eTG and tTG before and after introduction of a GFD were not examined in the same patients., Conclusion: Our data suggest that antibodies to eTG are the most sensitive serologic marker in treated and untreated patients with DH and confirm the central role of eTG in the pathogenesis of this disease.
- Published
- 2009
- Full Text
- View/download PDF
18. Propofol concentration in exhaled air and arterial plasma in mechanically ventilated patients undergoing cardiac surgery.
- Author
-
Grossherr M, Hengstenberg A, Meier T, Dibbelt L, Igl BW, Ziegler A, Schmucker P, and Gehring H
- Subjects
- Adult, Aged, Anesthetics, Intravenous administration & dosage, Anesthetics, Intravenous blood, Breath Tests methods, Chromatography, High Pressure Liquid methods, Dose-Response Relationship, Drug, Drug Monitoring methods, Female, Gas Chromatography-Mass Spectrometry methods, Humans, Male, Middle Aged, Pilot Projects, Propofol administration & dosage, Propofol blood, Young Adult, Anesthetics, Intravenous pharmacokinetics, Cardiac Surgical Procedures, Monitoring, Intraoperative methods, Propofol pharmacokinetics, Respiration, Artificial
- Abstract
Background: Measuring propofol concentration in plasma (c(P)PL) and in exhaled alveolar gas (c(P)G) during constant infusion provides information about their respective time courses. In the present study, we compared these time courses in patients undergoing cardiac surgery from the beginning of propofol anaesthesia until eye opening upon awakening., Methods: The c(P)G was measured before, during, and after continuous infusion of propofol for general anaesthesia in 12 patients at two randomly allocated doses (3 or 6 mg kg(-1) h(-1)). Gas samples were collected on Tenax tubes. After thermodesorption, c(P)G was measured by gas chromatography mass spectrometry. Simultaneously with exhaled gas, arterial blood was sampled for measuring c(P)PL by reversed-phase high-performance liquid chromatography with fluorescence detection. In order to compare the time courses of c(P)PL and c(P)G as dimensionless values directly, each gas and plasma value was normalized by relating it to the corresponding value at the end of the initial infusion after 40 min., Results: The c(P)G ranged between 2.8 and 22.5 ppb, whereas the corresponding c(P)PL varied between 0.3 and 3.3 microg ml(-1). Normalized concentration values showed a delayed increase in c(P)G compared with c(P)PL under constant propofol infusion before the onset of cardiopulmonary bypass, and a delayed decrease after stopping the propofol at the end of anaesthesia., Conclusions: Propofol can be measured in exhaled gas from the beginning until the end of propofol anaesthesia. The different time courses of c(P)PL and c(P)G have to be considered when interpreting c(P)G.
- Published
- 2009
- Full Text
- View/download PDF
19. What do we mean by 'replication' and 'validation' in genome-wide association studies?
- Author
-
Igl BW, Konig IR, and Ziegler A
- Subjects
- Humans, Reproducibility of Results, Terminology as Topic, Genome, Human, Genome-Wide Association Study statistics & numerical data, Research Design, Validation Studies as Topic
- Abstract
It has been acknowledged that results from genome-wide association studies need to be reproduced in further independent samples. This includes both aspects of replication and validation. Although often used interchangeably, both of these terms have a specific unique meaning and are not synonyms. Based on a number of applications from the literature producing a certain amount of confusion, our aim therefore is to clarify the definition of 'replication' and 'validation' and propose standards of their usage., (Copyright 2008 S. Karger AG, Basel.)
- Published
- 2009
- Full Text
- View/download PDF
20. [The influence of bone quality and the fixation procedure on the primary stability of cementless implanted tibial plateaus].
- Author
-
Boos C, Fink K, Stomberg P, Koeller W, Igl BW, and Russlies M
- Subjects
- Cementation, Humans, Motion, Treatment Outcome, Joint Instability physiopathology, Joint Instability prevention & control, Knee Joint physiopathology, Knee Joint surgery, Knee Prosthesis, Tibia surgery
- Abstract
Background: An overview of prospective studies on cementless and cemented primary knee joint endoprosthetics carried out between 1988 and 2004 reveals that the aseptic tibial loosening rate of cemented prostheses implanted with fixed meniscal bearings amounts to 2-6% within a period of 4-14 years, while cementless implanted prostheses show loosening rates of up to 28% within a period of 4-10 years. If these results arise from a lack of proper initial osseointegration as a result of insufficient primary stability, and how this is influenced by the tibial bone quality and the tibial fixation procedure has not yet been investigated., Materials and Methods: Tibial plateaus were press-fit implanted, both screwed and unscrewed, into each of six pairs of tibial heads from corpses. Stability testing was conducted applying eccentric axial load, shear and torsion., Results: The average amounts of relative movement at the medial and lateral plateau are clearly different in the screwed version and the unscrewed version when loaded axially, but the difference was significant (p = 0.016) only at the medial plateau. Relative movements under shear and torsion showed no significant differences. The bone density of the tibial metaphyses had no significant effect on the primary stability of the cementless implanted tibial plateau., Conclusion: When using cementless knee endoprostheses, the fixation of the tibial plateau with screws--in addition to a flawless press-fit and form-fit customization of the tibial head--appears indispensable for guaranteeing proper osseointegration under physiological axial loads.
- Published
- 2008
- Full Text
- View/download PDF
21. Genetic association studies for gene expressions: permutation-based mutual information in a comparison with standard ANOVA and as a novel approach for feature selection.
- Author
-
Szymczak S, Nuzzo A, Fuchsberger C, Schwarz DF, Ziegler A, Bellazzi R, and Igl BW
- Abstract
Mutual information (MI) is a robust nonparametric statistical approach for identifying associations between genotypes and gene expression levels. Using the data of Problem 1 provided for the Genetic Analysis Workshop 15, we first compared a quantitative MI (Tsalenko et al. 2006 J Bioinform Comput Biol 4:259-4) with the standard analysis of variance (ANOVA) and the nonparametric Kruskal-Wallis (KW) test. We then proposed a novel feature selection approach using MI in a classification scenario to address the small n - large p problem and compared it with a feature selection that relies on an asymptotic chi2 distribution. In both applications, we used a permutation-based approach for evaluating the significance of MI. Substantial discrepancies in significance were observed between MI, ANOVA, and KW that can be explained by different empirical distributions of the data. In contrast to ANOVA and KW, MI detects shifts in location when the data are non-normally distributed, skewed, or contaminated with outliers. ANOVA but not MI is often significant if one genotype with a small frequency had a remarkable difference in the average gene expression level relative to the other two genotypes. MI depends on genotype frequencies and cannot detect these differences. In the classification scenario, we show that our novel approach for feature selection identifies a smaller list of markers with higher accuracy compared to the standard method. In conclusion, permutation-based MI approaches provide reliable and flexible statistical frameworks which seem to be well suited for data that are non-normal, skewed, or have an otherwise peculiar distribution. They merit further methodological investigation.
- Published
- 2007
- Full Text
- View/download PDF
22. The intraindividual agreement of the bone density of the human proximal tibia.
- Author
-
Boos C, Fink K, Stomberg P, Köller W, Igl BW, and Russlies M
- Subjects
- Densitometry, Female, Humans, Male, Middle Aged, Reproducibility of Results, Sensitivity and Specificity, Tibia cytology, Bone Density, Tibia anatomy & histology
- Abstract
The interindividual variability in the biomechanical properties of cadaver bones has remained an unsolved problem in biomechanical investigation procedures. For this reason, it is postulated to use matched bone pairs from the same individual for comparative biomechanical tests. The rationale behind this procedure is based on the assumption that biomechanically similar behaviour is to be expected in an intraindividual rather than an interindividual comparison. Systematic studies confirming this thesis were performed on the human femur. However, investigations regarding the intraindividual properties of the proximal tibial metaphysis with respect to the underlying bone densities, have not yet been performed. In order to verify the hypothesis that matched proximal tibial metaphyses from the same donor imply corresponding bone density values, densitometric measurements (pQCT) were performed in 14 matched cadaver tibias (average age 61 years, 9 men, 5 women) which were fresh-frozen at -40 degrees C after removal. After statistical analysis of the bone density values, five tibial pairs were identified as differing on the basis of missing correlations and the existence of systematic differences within the pairwise data. In other words, only about 2/3 of the data in the random sample available was classified as comparable. As the bone density measured by pQCT technique significantly correlates with the biomechanical properties of the bone, it can be concluded from the test result available that matched human tibiae show no concurring bone density values in 1/3 of cases. Thus the pairing of corpse tibiae does not necessarily imply suitability for comparative biomechanical experiments.
- Published
- 2007
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.