Publikationen von Sandra Freitag-Wolf
Rubin D, Helwig U, Pfeuffer M, Auinger A, Ruether A, Matusch D, Darabaneanu S, Freitag-Wolf S, Nothnagel M, Schreiber S, Schrezenmeir J.
The effect of FABP2 promoter haplotype on response to a diet with medium-chain triacylglycerols.Genes Nutr,
(2012).
[abstract]
Abstract:
The fatty-acid-binding protein-2 (FABP2) gene has been proposed as a candidate gene for diabetes because the encoded protein is involved in fatty acid absorption and therefore may affect insulin sensitivity and glucose metabolism. The rare haplotype (B) of its promoter was shown to be associated with a lower risk for type 2 diabetes. The aim of this study was to investigate whether a polymorphism in the FABP2 promoter does affect the metabolic response to either an medium-chain triacylglycerol (MCT) or an long-chain triacylglycerol (LCT) diet, which were suggested to differ in transport mechanisms, in affinity to FABP2, in activating transcription factors binding to the FABP2 promoter and in their effects on insulin sensitivity. We studied 82 healthy male subjects varying in the FABP2 promoter (42 homozygous for common haplotype (A), 40 homozygous for the rare haplotype (B)) in an interventional study with either an MCT or LCT diet over 2 weeks to examine gene-nutrient interaction. The saturation grade of MCT was adjusted to that of the LCT fat. We determined glucose, insulin, triacylglycerols (TGs), chylomicron triacylglycerols and cholesterol before and after a standardised mixed meal before and after the intervention. HDL cholesterol increased in all groups, which was most pronounced in subjects homozygous for the common promoter haplotype A who received MCT diet (P = 0.001), but not significant in homozygous rare haplotype B subjects who received MCT fat. Subjects homozygous for FABP2 haplotype A showed a significant decrease in fasting and postprandial glucose (P = 0.01, 0.04, respectively) and a decrease in insulin resistance (HOMA-IR, P = 0.04) during LCT diet. After correction for multiple testing, those effects did not remain significant. Fasting and postprandial triacylglycerols, LDL cholesterol, chylomicron TGs and cholesterol were not affected by genotype or diet. MCT diet increased HDL cholesterol dependent on the FABP2 promoter haplotype. The effects of the promoter haplotype B could be mediated by PPARγ, which is upregulated by medium-chain fatty acids.
Habermann JK, Brucker CA, Freitag-Wolf S, Heselmeyer-Haddad K, Krüger S, Barenboim L, Downing T, Bruch HP, Auer G, Roblick UJ, Ried T.
Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma.Mod Pathol,
24 (2011), 542-55.
[abstract]
Abstract:
Individual colorectal adenomas have different propensities to progress to invasive disease. In this study, we explored whether these differences could be explained by gene copy number alterations. We evaluated 18 adenomas of patients without synchronous or subsequent carcinoma (6.5 years follow-up), 23 adenomas of carcinoma patients, and 6 related carcinomas. All samples were measured for their DNA ploidy status. Centromere probes for chromosomes 17 and 18, as well as gene-specific probes for SMAD7, EGFR, NCOA3, TP53, MYC, and RAB20 were assessed by multicolor fluorescence in situ hybridization. An increased genomic instability index of CEP17, SMAD7, and EGFR, as well as TP53 deletions and MYC amplifications defined adenomas of patients with synchronous carcinoma (P<0.05). Diploid NCOA3 signal counts were associated with longer adenoma recurrence-free surveillance (P=0.042). In addition, NCOA3, MYC, EGFR, and RAB20 amplifications, as well as TP53 deletions correlated with increased DNA stem line values and/or aneuploidy in adenomas (P<0.05). Furthermore, aberrations of NCOA3, MYC, and RAB20 were associated with histopathologically defined high-risk adenomas (P<0.05). RAB20 amplifications were also correlated with high-grade dysplastic adenomas (P=0.002). We conclude that genomic instability in colorectal adenomas is reflected by EGFR, MYC, NCOA3, and RAB20 amplifications that do correlate with histomorphological features and are indicative for adenoma recurrence and the presence of synchronous carcinomas.
Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T.
Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice.Ann Rheum Dis,
70 (2011), 844-50.
[abstract]
Abstract:
These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.
Harder S, Dimaczek B, Açil Y, Terheyden H, Freitag-Wolf S, Kern M.
Molecular leakage at implant-abutment connection--in vitro investigation of tightness of internal conical implant-abutment connections against endotoxin penetration.Clin Oral Investig,
14 (2010), 427-32.
[abstract]
Abstract:
Microleakage has been discussed as a major contributing factor for inflammatory reactions at the implant-abutment connection. In previous studies, the tightness against corpuscular bodies (viable bacteria) has been successfully investigated under static and dynamic conditions. The aim of this study was to investigate the tightness against endotoxins of two implant systems (AstraTech and Ankylos) with conical internal connections under static conditions. The inner parts of eight implants of each system were inoculated with endotoxin. Implants were screwed together with the respective abutments and stored under isostatic conditions in a supernatant of pyrogen-free water for 168 h. Supernatant samples were taken after 5 min, 24 h, 72 h, and 168 h, and endotoxin contamination was determined by the amebocyte-lysate test. Only one implant in the AstraTech group showed no sign of endotoxin contamination after 168 h, while the other implants showed contamination after varying storage times, respectively. The implants in the Ankylos group showed endotoxin contamination after only 5 min of storage in the supernatant solution. The tested internal conical implant-abutment connections appear to be unable to prevent endotoxin leakage. In average, Astra implants showed a higher tightness than Ankylos implants.
Biederer J, Bolte H, Schmidt T, Charalambous N, Both M, Kopp U, Hoffmann B, Freitag-Wolf S, Van Metter R, Heller M.
Detection of Artificial Air Space Opacities with Digital Radiography: Ex Vivo Study on Enhanced Latitude Post-Processing.Rofo,
(2010).
[abstract]
Abstract:
PURPOSE: To evaluate in a.-p. digital chest radiograms of an ex vivo system if increased latitude and enhanced image detail contrast (EVP) improve the accuracy of detecting artificial air space opacities in parts of the lung that are superimposed by the diaphragm. MATERIALS AND METHODS: 19 porcine lungs were inflated inside a chest phantom, prepared with 20 - 50 ml gelatin-stabilized liquid to generate alveolar air space opacities, and examined with direct radiography (3.0 x 2.5 k detector/ 125 kVp/ 4 mAs). 276 a.-p. images with and without EVP of 1.0 - 3.0 were presented to 6 observers. 8 regions were read for opacities, the reference was defined by CT. Statistics included sensitivity/specificity, interobserver variability, and calculation of Az (area under ROC curve). RESULTS: Behind the diaphragm (opacities in 32 / 92 regions), the median sensitivity increased from 0.35 without EVP to 0.53 - 0.56 at EVP 1.5 - 3.0 (significant in 5 / 6 observers). The specificity decreased from 0.96 to 0.90 (significant in 6 / 6), and the Az value and interobserver correlation increased from 0.66 to 0.74 and 0.39 to 0.48, respectively. Above the diaphragm, the median sensitivity for artificial opacities (136 / 276 regions) increased from 0.71 to 0.77 - 0.82 with EVP (significant in 4 / 6 observers). The specificity and Az value decreased from 0.76 to 0.62 and 0.74 to 0.70, respectively, (significant in 3 / 6). CONCLUSION: In this ex vivo experiment, EVP improved the diagnostic accuracy for artificial air space opacities in the superimposed parts of the lung (area under the ROC curve). Above the diaphragm, the accuracy was not affected due to a tradeoff in sensitivity/specificity.
Mehl C, Kern M, Freitag-Wolf S, Wolfart M, Brunzel S, Wolfart S.
Does the oral health impact profile questionnaire measure dental appearance?.Int J Prosthodont,
22 (2009 Jan-Feb), 87-93.
[abstract]
Abstract:
PURPOSE: The aim of this study was to evaluate whether there is a need to develop a new questionnaire measuring dental appearance or if this is already covered by the Oral Health Impact Profile (OHIP-49). MATERIALS AND METHODS: Based on internationally accepted guidelines about dental esthetics, a questionnaire was developed to measure dental appearance (QDA). Eleven items defined a QDA sum score (0 = absolutely satisfied, 44 = absolutely dissatisfied). Furthermore, oral health-related quality of life was evaluated using the German version of the OHIP-49 and the OHIP-esthetic. Thirty patients (14 women, 16 men; mean age 59 +/- 10 years) were included in the study. All patients received a complete oral rehabilitation including the anterior teeth of the maxilla. Questionnaires were completed before and after treatment. RESULTS: The median values were 16 and 1.5 for the QDA sum score, 46 and 16 for the OHIP sum score, and 14.5 and 2 for the OHIP-esthetic before and after rehabilitation, respectively. The improvement after treatment was significant for all questionnaires (P < or = .0001). Between the QDA sum score and the OHIP sum score or any of the OHIP subscales (the only exception being "psychological discomfort"), no significant correlation could be found (P > .05). Between the QDA sum score and the OHIP-esthetic, a significant correlation could be found before treatment (r = 0.505, P = .004) but not after treatment (P > .05). CONCLUSIONS: If the OHIP-49 is used in clinical studies and a profound evaluation of dental appearance is desired, it is reasonable to use an additional esthetic modulus.
Häsler R, Begun A, Freitag-Wolf S, Kerick M, Mah N, Zvirbliene A, Spehlmann ME, von Wurmb-Schwark N, Kupcinskas L, Rosenstiel P, Schreiber S.
Genetic control of global gene expression levels in the intestinal mucosa - a human twin study.Physiol Genomics,
(2009).
[abstract]
Abstract:
Phenotypic variation between individuals, such as different mRNA expression levels, is influenced by genetic and non-genetic factors. Although several studies have addressed the interplay between genotypes and expression profiles in various model organisms in the recent years, the detailed and relative contributions of genetic and non-genetic factors in regulating plasticity of gene expression in barrier organs (e.g. skin, gut) which are exposed to continuous environmental challenge, are still poorly understood. Here we systematically monitor the level of genetic control over genome-wide mRNA expression profiles in the healthy intestinal mucosa of 10 monozygotic and 10 dizygotic human twin pairs using microarray analyses. Our results, which are supported by real time PCR verification and the analysis of molecular phylogenetic conservation, indicate that genes associated with energy metabolism and cell and tissue regeneration pathways are under strong genetic control. Conversely, genes associated with immune response seem to be mainly controlled by exogenous factors. Further insights into the relative extent of genetic and non-genetic determinants of transcriptomal profiles and their influence on physiological and pathophysiological mechanisms are crucial to understanding the key-role played by gene-environmentinteractions in health and disease. Key words: Gene Expression Profiling, Genome, Primary Tissue, Twins.
Lu TT, Lao O, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Nielsen F, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Ruether A, Schreiber S, Becker C, Nürnberg P, Nelson MR, Kayser M, Krawczak M.
An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population.Eur J Hum Genet,
17 (2009), 967-75.
[abstract]
Abstract:
Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics advance online publication, 21 January 2009; doi:10.1038/ejhg.2008.266.
Fritsche LG, Freitag-Wolf S, Bettecken T, Meitinger T, Keilhauer CN, Krawczak M, Weber BH.
Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene.Hum Mutat,
30 (2009), 1048-53.
[abstract]
Abstract:
Age-related macular degeneration (AMD) is a frequent, multifactorial disease of the central retina and a major cause of irreversible vision loss in industrialized countries. Apolipoprotein E (APOE) has been consistently associated with AMD, particularly its two functional isoforms E2 (predisposing) and E4 (protective). The biological correlate of this association, however, is still unclear. In this study, we have defined an extended haplotype block encompassing the entire APOE gene locus, including known coding as well as cis-regulatory promoter variants. Of the five extended APOE haplotypes common in the general population, two were found to be significantly associated with AMD, namely G-G-G-G-epsilon2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.12) and T-G-A-G-epsilon4 (OR, 0.76; 95% CI, 0.58-0.99). When analyzing common extended haplotype combinations, T-C-G-G-epsilon3/T-G-A-G-epsilon4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20-0.51). Intriguingly, we also found one extended epsilon3-haplotype, G-G-G-A-epsilon3, to be protective in the homozygous state (OR, 0.65; 95% CI, 0.49-0.87). Since single nucleotide polymorphism (SNP) rs405509:G>T is a constituent of the extended epsilon-haplotype block and is known to significantly influence APOE promoter activity, we hypothesize that both the relative rate of APOE isoform expression in conjunction with established functional differences of the respective isoforms may be crucial in mediating AMD pathology. This would also imply that genotyping of the core epsilon-haplotypes alone is not sufficient to estimate AMD risk, but that determination of extended haplotype combinations, including the functional promoter SNP rs405509, is required instead.
Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Rüther A, Schreiber S, Becker C, Nürnberg P, Nelson MR, Krawczak M, Kayser M.
Correlation between genetic and geographic structure in Europe.Curr Biol,
18 (2008), 1241-8.
[abstract]
Abstract:
Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry.
Herber-Jonat S, von Bismarck P, Freitag-Wolf S, Nikischin W.
Limitation of measurements of expiratory tidal volume and expiratory compliance under conditions of endotracheal tube leaks.Pediatr Crit Care Med,
9 (2008), 69-75.
[abstract]
Abstract:
OBJECTIVE: Endotracheal tube leaks (ETTLs) occur in neonates ventilated with uncuffed tubes. Assuming that the influence of ETTLs might be neglected during expiration, only expiratory tidal volume is measured for calculation of expiratory compliance in cases of large ETTLs. However, expiratory ETTL might be substantial. Therefore, we evaluated the effect of ETTL size on expiratory tidal volume and compliance. DESIGN: Prospective laboratory study and retrospective clinical study. SETTING: University research laboratory and neonatal intensive care unit. PATIENTS: Sixty ventilated neonates (weight 640-2160 g, gestational age 25-33 wks) were investigated. INTERVENTIONS: The impact of increasing ETTLs on inspiratory and expiratory measured tidal volume (Vm), corrected tidal volume (Vc), and leak volume (Vl) was investigated in a ventilated neonatal lung model. The range of ETTLs (1% to 95%) was subdivided into five groups of 12 infants each. Furthermore, the relationships between standard ETTL size and inspiratory and expiratory ETTLs were evaluated using nonlinear regression. Standard ETTL size was defined as the difference between measured inspiratory and expiratory tidal volume (Vm) related to inspiratory Vm. MEASUREMENTS AND MAIN RESULTS: The size of a standard ETTL was 40% when expiratory ETTL reached 10% and was 12% when the inspiratory ETTL reached 10%. In infants, the differences between Vm and Vc were statistically significant during inspiration in the group beginning at a standard ETTL of 41% and during expiration in the group beginning at a standard ETTL of 69% (p < .05). Results of nonlinear regression showed that the standard ETTL was 33% (95% confidence interval, 28% to 36%) when expiratory ETTL reached 10% and was 13% (95% confidence interval, 12% to 15%) when inspiratory ETTL reached 10%. CONCLUSIONS: Expiratory Vl has a relevant impact if a certain ETTL size is reached.
Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B.
Standardized quantification of pulmonary fibrosis in histological samples.Biotechniques,
44 (2008), 507-11, 514-7.
[abstract]
Abstract:
The Ashcroft scale for the evaluation of bleomycin-induced lung fibrosis is the analysis of stained histological samples by visual assessment. Based on the knowledge that this procedure is not standardized in animals and results are highly variable, we hypothesized that modification of this method may improve quantification of lung fibrosis in small animals. To prove our hypothesis, we evaluated pulmonary fibrosis in Lewis rats induced by a single intratracheal injection of 0.3 mg/kg body weight bleomycin (n = 13) compared with the same amount of saline in a control group (n = 4). We modified the Ashcroft scale by precisely defining the assignment of grades from 0 to 8 for the increasing extent of fibrosis in lung histological samples. Thirty-two observers were randomly assigned to evaluate 108 photographs of slides using either the Ashcroft scale or the modified scale. Consistent with our hypothesis, there was a significant reduction in the variability of standard deviations with the modified scale compared with the Ashcroft scale (mean of variability 0.25 versus 0.62, P < 0.0001). Applying the kappa index, the Ashcroft scale showed only a fair to moderate agreement (0.23-0.59) between the observers and a low intra-observer agreement (0.51-0.74) in contrast to the modified scale, which demonstrated a moderate to good agreement between the observers (0.65-0.93, P < 0.0001) and a high intra-observer agreement (0.87-0.91, P < 0.05). To test the modified scale in vivo, we compared both scales with the results of computed tomography (CT) of the lungs obtained from the same mice. In agreement, the modified scale demonstrated a better correlation to CT scans (R = 0.58) compared with the Ashcroft scale (R = 0.33). In summary, quantification of lung fibrosis in histological lung sections using the modified scale is reliable and reproducible.
Schafmayer C, Freitag-Wolf S, Wolken H, Buch S, Brosch M, Egberts JH, Shekarriz H, Fölsch UR, Fändrich F, Krawczak M, Schreiber S, Tepel J, Hampe J.
Increased heritability of gallstone disease in early onset cases.Liver Int,
28 (2008), 895-7.
Hübner RH, El Mokhtari NE, Freitag S, Rausche T, Göder R, Tiroke A, Lins M, Simon R, Bewig B.
NT-proBNP is not elevated in patients with obstructive sleep apnoea.Respir Med,
102 (2008), 134-42.
[abstract]
Abstract:
BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-ProBNP) has emerged as an important marker of cardiac stress and may reflect the severity of underlying cardiac dysfunction, which is thought to be associated with obstructive sleep apnoea syndrome (OSAS). METHODS: This study evaluated the plasma concentration of NT-ProBNP in 60 consecutive patients (median age 55.7 years, median body mass index (BMI) 31.8) who were referred to a sleep laboratory with a suspicion of OSAS. Each subject underwent measurement of morning NT-ProBNP plasma levels, polysomnography and echocardiography. Patients were treated with nasal continuous or bilevel positive airway pressure ventilation (nCPAP/BIPAP) or without mechanical respiratory support, depending on clinical symptoms and results of polysomnography. Three months after treatment of OSAS 28 of the patients were reassessed for re-evaluation of NT-ProBNP and polysomnography. RESULTS: Low or high levels of NT-proBNP were not associated with AHI and other sleep related indices (p>0.3). There was no correlation between NT-proBNP and AHI or other sleep related indices. In multiple regression analysis, NT-proBNP was significantly correlated with left ventricular ejection fraction, creatinine clearance and the presence of systemic arterial hypertension but not with AHI. CONCLUSIONS: Our results show by a robust multiple regression analysis, that NT-pro BNP is not associated with OSAS and NT-pro BNP cannot be used as a sensitive marker for underlying cardiovascular abnormalities in patients with OSAS.
Bolte H, Riedel C, Knöss N, Freitag S, Hoffmann B, Heller M, Biederer J.
Computed tomography-based lung nodule volumetry--do optimized reconstructions of routine protocols achieve similar accuracy, reproducibility and interobserver variability to that of special volumetry protocols?.Rofo,
179 (2007), 276-81.
[abstract]
Abstract:
PURPOSE: The aim of this in vitro and ex vivo CT study was to investigate whether the use of a routine thorax protocol (RTP) with optimized reconstruction parameters can provide comparable accuracy, reproducibility and interobserver variability of volumetric analyses to that of a special volumetry protocol (SVP). MATERIALS AND METHODS: To assess accuracy, 3 polyurethane (PU) spheres (35 HU; diameters: 4, 6 and 10 mm) were examined with a recommended SVP using a multislice CT (collimation 16 x 0.75 mm, pitch 1.25, 20 mAs, slice thickness 1 mm, increment 0.7 mm, medium kernel) and an optimized RTP (collimation 16 x 1.5 mm, pitch 1.25, 100 mAs, reconstructed slice thickness 2 mm, increment 0.4 mm, sharp kernel). For the assessment of intrascan and interscan reproducibility and interobserver variability, 20 artificial small pulmonary nodules were placed in a dedicated ex vivo chest phantom and examined with identical scan protocols. The artificial lesions consisted of a fat-wax-Lipiodol mixture. Phantoms and ex vivo lesions were examined afterwards using commercial volumetry software. To describe accuracy the relative deviations from the true volumes of the PU phantoms were calculated. For intrascan and interscan reproducibility and interobserver variability, the 95 % normal range (95 % NR) of relative deviations between two measurements was calculated. RESULTS: For the SVP the achieved relative deviations for the 4, 6 and 10 mm PU phantoms were - 14.3 %, - 12.7 % and - 6.8 % and were 4.5 %, - 0.6 % and - 2.6 %, respectively, for the optimized RTP. SVP showed a 95 % NR of 0 - 1.5 % for intrascan and a 95 % NR of - 10.8 - 2.9 % for interscan reproducibility. The 95 % NR for interobserver variability was - 4.3 - 3.3 %. The optimized RTP achieved a 95 % NR of - 3.1 - 4.3 % for intrascan reproducibility and a 95 % NR of - 7.0 - 3.5 % for interscan reproducibility. The 95 % NR for interobserver variability was - 0.4 - 6.8 %. CONCLUSION: For datasets achieved with an SVP and an optimized RTP, this experimental approach showed comparable accuracy, reproducibility, and interobserver variability to allow for sufficient volumetric analysis of pulmonary lesions.
Bolte H, Jahnke T, Schäfer FK, Wenke R, Hoffmann B, Freitag-Wolf S, Dicken V, Kuhnigk JM, Lohmann J, Voß S, Knöß N, Heller M, Biederer J.
Interobserver-variability of lung nodule volumetry considering different segmentation algorithms and observer training levels.Eur J Radiol,
64 (2007), 285-295.
[abstract]
Abstract:
OBJECTIVE: The aim of this study was to investigate the interobserver variability of CT based diameter and volumetric measurements of artificial pulmonary nodules. A special interest was the consideration of different measurement methods, observer experience and training levels. MATERIALS AND METHODS: For this purpose 46 artificial small solid nodules were examined in a dedicated ex-vivo chest phantom with multislice-spiral CT (20mAs, 120kV, collimation 16mmx0.75mm, table feed 15mm, reconstructed slice thickness 1mm, reconstruction increment 0.7mm, intermediate reconstruction kernel). Two observer groups of different radiologic experience (0 and more than 5 years of training, 3 observers each) analysed all lesions with digital callipers and 2 volumetry software packages (click-point depending and robust volumetry) in a semi-automatic and manually corrected mode. For data analysis the variation coefficient (VC) was calculated in per cent for each group and a Wilcoxon test was used for analytic statistics. RESULTS: Click-point robust volumetry showed with a VC of <0.01% in both groups the smallest interobserver variability. Between experienced and un-experienced observers interobserver variability was significantly different for diameter measurements (p=0.023) but not for semi-automatic and manual corrected volumetry. A significant training effect was revealed for diameter measurements (p=0.003) and semi-automatic measurements of click-point depending volumetry (p=0.007) in the un-experienced observer group. CONCLUSIONS: Compared to diameter measurements volumetry achieves a significantly smaller interobserver variance and advanced volumetry algorithms are independent of observer experience.
Biederer J, Gottwald T, Bolte H, Riedel C, Freitag S, Van Metter R, Heller M.
Pulmonary nodule detection with digital projection radiography: an ex-vivo study on increased latitude post-processing.Eur Radiol,
17 (2007), 1089-100.
[abstract]
Abstract:
To evaluate increased image latitude post-processing of digital projection radiograms for the detection of pulmonary nodules. 20 porcine lungs were inflated inside a chest phantom, prepared with 280 solid nodules of 4-8 mm in diameter and examined with direct radiography (3.0x2.5 k detector, 125 kVp, 4 mAs). Nodule position and size were documented by CT controls and dissection. Four intact lungs served as negative controls. Image post-processing included standard tone scales and increased latitude with detail contrast enhancement (log-factors 1.0, 1.5 and 2.0). 1280 sub-images (512x512 pixel) were centred on nodules or controls, behind the diaphragm and over free parenchyma, randomized and presented to six readers. Confidence in the decision was recorded with a scale of 0-100%. Sensitivity and specificity for nodules behind the diaphragm were 0.87/0.97 at standard tone scale and 0.92/0.92 with increased latitude (log factor 2.0). The fraction of "not diagnostic" readings was reduced (from 208/1920 to 52/1920). As an indicator of increased detection confidence, the median of the ratings behind the diaphragm approached 100 and 0, respectively, and the inter-quartile width decreased (controls: p<0.001, nodules: p=0.239) at higher image latitude. Above the diaphragm, accuracy and detection confidence remained unchanged. Here, the sensitivity for nodules was 0.94 with a specificity from 0.96 to 0.97 (all p>0.05). Increased latitude post-processing has minimal effects on the overall accuracy, but improves the detection confidence for sub-centimeter nodules in the posterior recesses of the lung.
Bolte H, Riedel C, Müller-Hülsbeck S, Freitag-Wolf S, Kohl G, Drews T, Heller M, Biederer J.
Precision of computer-aided volumetry of artificial small solid pulmonary nodules in ex vivo porcine lungs.Br J Radiol,
80 (2007), 414-21.
[abstract]
Abstract:
The purpose of this study was to investigate the precision of CT-based volumetric measurements of artificial small pulmonary nodules under ex vivo conditions. We implanted 322 artificial nodules in 23 inflated ex vivo porcine lungs in a dedicated chest phantom. The lungs were examined with a multislice spiral CT (20 mAs, collimation 16x0.75 mm, 1 mm slice thickness, 0.7 mm increment). A commercial volumetry software package (LungCARE VA70C-W; Siemens, Erlangen, Germany) was used for volume analysis in a semi-automatic and a manual corrected mode. After imaging, the lungs were dissected to harvest the nodules for gold standard determination. The volumes of 202 solitary, solid and well-defined lesions without contact with the pleura, greater bronchi or vessels were compared with the results of volumetry. A mean nodule diameter of 8.3 mm (+/-2.1 mm) was achieved. The mean relative deviation from the true lesion volume was -9.2% (+/-10.6%) for semi-automatic and -0.3% (+/-6.5%) for manual corrected volumetry. The subgroup of lesions from 5 mm to <10 mm in diameter showed a mean relative deviation of -8.7% (+/-10.9%) for semi-automatic volumetry and -0.3% (+/-6.9%) for manually corrected volumetry. We conclude that the presented software allowed for precise volumetry of artificial nodules in ex vivo lung tissue. This result is comparable to the findings of previous in vitro studies.
Wolfart S, Quaas AC, Freitag S, Kropp P, Gerber WD, Kern M.
General well-being as an important co-factor of self-assessment of dental appearance.Int J Prosthodont,
19 (2006 Sep-Oct), 449-54.
[abstract]
Abstract:
PURPOSE: This study aimed to correlate the general well-being of patients and their judgment about their dental appearance. MATERIALS AND METHODS: Based on internationally accepted guidelines regarding dental esthetics, a questionnaire was developed to measure subjective assessments of dental appearance. Fourteen items defined an esthetic sum score (0 = satisfied; 56 = dissatisfied). Further, general well-being was evaluated with a long-established and highly reliable test. Eighty participants were included (47 women, 33 men). Participants were.drawn from 4 different groups (n = 20): natural dentition (group N), fixed partial dentures (group F), removable partial dentures (group R), and patients who had an esthetic problem with their teeth (group P). RESULTS: Seventy-five participants showed a normal well-being. Five participants showed a depressive state and formed a new group (group D). The medians of the sum scores (25th, 75th percentile) were: group N: 12 (10, 14); group F: 14 (8, 29); group R: 14 (9, 27); group P: 23 (18, 35); group D: 30 (26, 35). Significant differences were found between groups N and P, as well as between group D and groups N, F, and R. CONCLUSION: Because of the significant difference between groups N and P, basis validation of the sum score was achieved. Further, self-assessments of dental appearance appeared to be more negative for participants with a depressive state compared with the other groups. In clinical studies, selection bias can be prevented by using a test that measures well-being to verify if a study sample includes a normal number of depressive subjects and therefore represents the general population.
Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S, Rehman A, Kühbacher T, Nikolaus S, Namsolleck P, Blaut M, Hampe J, Sahly H, Reinecke A, Haake N, Günther R, Krüger D, Lins M, Herrmann G, Fölsch UR, Simon R, Schreiber S.
Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.Circulation,
113 (2006), 929-37.
[abstract]
Abstract:
BACKGROUND: Bacterial infection has been discussed as a potential etiologic factor in the pathophysiology of coronary heart disease (CHD). This study analyzes molecular phylogenies to systematically explore the presence, frequency, and diversity of bacteria in atherosclerotic lesions in patients with CHD. METHODS AND RESULTS: We investigated 16S rDNA signatures in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients with CHD, control material from postmortem patients (n=15), and heart-beating organ donors (n=11) using clone libraries, denaturating gradient gel analysis, and fluorescence in situ hybridization. Bacterial DNA was found in all CHD patients by conserved PCR but not in control material or in any of the normal/unaffected coronary arteries. Presence of bacteria in atherosclerotic lesions was confirmed by fluorescence in situ hybridization. A high overall bacterial diversity of >50 different species, among them Staphylococcus species, Proteus vulgaris, Klebsiella pneumoniae, and Streptococcus species, was demonstrated in >1500 clones from a combined library and confirmed by denaturating gradient gel analysis. Mean bacterial diversity in atheromas was high, with a score of 12.33+/-3.81 (range, 5 to 22). A specific PCR detected Chlamydia species in 51.5% of CHD patients. CONCLUSIONS: Detection of a broad variety of molecular signatures in all CHD specimens suggests that diverse bacterial colonization may be more important than a single pathogen. Our observation does not allow us to conclude that bacteria are the causative agent in the etiopathogenesis of CHD. However, bacterial agents could have secondarily colonized atheromatous lesions and could act as an additional factor accelerating disease progression.
Brunzel S, Kern M, Freitag S, Wolfart S.
Aesthetic effect of minor changes in incisor angulation: an internet evaluation.J Oral Rehabil,
33 (2006), 430-5.
[abstract]
Abstract:
The aim of this study was to evaluate the aesthetic assessment of different tiltings of the upper incisors with surrounding tissues. A picture of a smiling mouth revealing the upper anterior teeth from 15 to 25 was digitally transformed producing different tiltings of the incisors. These seven versions presented in a web-based survey were evaluated concerning their attractiveness. Overall 439 judges joined the evaluation. However, 249 judges were included in analysis, because only judges with normal wellbeings and completed questionnaires were accepted. These judges consisted of 38 dentists, 26 dental and 24 other students, 45 academics and 89 non-academics, while 27 gave no data about their profession. The results [median (first; third quartile)] showed significant that symmetrical incisors [67.5 (47.5; 85.0)] and minor changes in the angulation of one [65.0 (42.5; 80.0)] or both lateral incisors [65.0 (42.5; 80.0)], respectively, are aesthetically more attractive than the angulation of one [45.0 (27.5; 62.5)] or both central incisors [27.5 (16.3; 45.0)], or the combination of one tilted lateral and central incisor [37.5 (25.0; 60.0)]. These results confirm the results of a previous study where similar image versions without surrounding tissues were assessed concerning their attractiveness on printed photos.
Rubin D, Helwig U, Pfeuffer M, Schreiber S, Boeing H, Fisher E, Pfeiffer A, Freitag-Wolf S, Foelsch UR, Doering F, Schrezenmeir J.
A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.J Hum Genet,
51 (2006), 567-74.
[abstract]
Abstract:
The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B-containing lipoproteins. Emerging evidence has indicated that the functional MTP exon polymorphism I128T is associated with dyslipidemia and other traits of the insulin-resistance syndrome, and the T128 variant seems to confer a reduced stability of MTP, resulting in reduced binding of LDL particles. The aim of the study was to elucidate the association of this MTP polymorphism with parameters of postprandial metabolism. A total of 716 male subjects from a postprandially characterized cohort (MICK) and a nested case-control study (EPIC) of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls were genotyped for the I128T exon polymorphism. In comparison to homozygote subjects of the wild allele, carriers of the less common allele of the MTP T128 genotype showed significantly lower postprandial insulin levels (P=0.017), lower diastolic blood pressure (P=0.049) and had a lower prevalence of impaired glucose metabolism and diabetes type 2 (P=0.03) in the MICK. Consistent with this, we found a lower incidence of type 2 diabetes in male subjects of the nested case-control study in the T128 genotype (P=0.007). These results suggest that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes and other parameters of the metabolic syndrome.
Stock UA, Degenkolbe I, Attmann T, Schenke-Layland K, Freitag S, Lutter G.
Prevention of device-related tissue damage during percutaneous deployment of tissue-engineered heart valves.J Thorac Cardiovasc Surg,
131 (2006), 1323-30.
[abstract]
Abstract:
BACKGROUND: Endovascular application of pulmonary heart valves has been recently introduced clinically. A tissue-engineering approach was pursued to overcome the current limitations of bovine jugular vein valves (degeneration and limited longevity). However, deployment of the delicate tissue-engineered valves resulted in severe tissue damage. Therefore the objective of this study was to prevent tissue damage during the folding and deployment maneuver. MATERIAL AND METHODS: Porcine pulmonary heart valves, small intestinal submucosa, and ovine carotid arteries were obtained from a slaughterhouse. After dissection and antimicrobial incubation, the valves were trimmed (removal of sinus and most of the muscular ring) to fit into the deployment catheter. The inside (in-stent group, n = 6) or outside (out-stent group, n = 6) of a nitinol stent was covered by an acellular small intestinal submucosa, and the valves were sutured into the stent. The valves were folded, tested for placement in the deployment catheter, and decellularized enzymatically. Myofibroblasts were obtained from carotid artery segments and seeded onto the scaffolds. The seeded constructs were placed in a dynamic bioreactor system and cultured for 16 consecutive days. After endothelial cell seeding, the constructs were folded, deployed, and processed for histology and surface electron microscopy. RESULTS: The valves opened and closed competently throughout the entire dynamic culture. Surface electron microscopy revealed an almost completely preserved tissue in the in-stent group. Stents covered with small intestinal submucosa on the outside, however, showed severe damage. CONCLUSION: This study demonstrates that small intestinal submucosa covering of the inside of a pulmonary valved stent can prevent stent strut-related tissue damage.
Bartsch T, Alfke K, Stingele R, Rohr A, Freitag-Wolf S, Jansen O, Deuschl G.
Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae.Brain,
129 (2006), 2874-84.
[abstract]
Abstract:
The aetiology, pathomechanisms and anatomical correlates of transient global amnesia (TGA) still remain obscure. Recently, focal MR-signal diffusion-weighted imaging (DWI) changes in the hippocampus have been described in patients with TGA, but the exact localization, long term outcome and pathophysiological nature of these lesions still remain unknown. The topography and time course of hippocampal DWI lesions in 41 TGA patients was studied using serial 3 T high-resolution MR-imaging and correlated to clinical and neuropsychometric results. Of these, 29 patients showed 36 DWI lesions with corresponding T(2) lesions in the hippocampus within a time window of 48 h after onset. Almost all lesions (94%; 34/36) were selectively found in the CA-1 sector (Sommer sector) of the hippocampal cornu ammonis. Most DWI lesions (8/10) were already detectable in the peri-acute phase <6 h after onset of symptoms. A follow-up study 4-6 months after the episode did not show evidence for residual structural sequelae of these lesions (n = 20/20). A venous MR angiography of the intracranial dural sinus showed an asymmetric venous drainage in 21/24 (88%) patients. In 11/16 (69%) patients with unilateral lesions, the asymmetry corresponded to the side of the DWI lesion. Significant episodic verbal memory deficits in the acute phase (n = 14/18) were associated with lesions of the dominant hemisphere while impairment of visuospatial memory was associated with lesions of the non-dominant hemisphere. Persistent neuropsychological sequelae were not detected 4-6 months after the episode (n = 16). This is the first prospective study combining high-resolution imaging and neuropsychometry analysing the detailed functional anatomy and outcome of hippocampal DWI/T(2) lesions in TGA supporting the view the TGA being a benign transient disorder. The TGA can be considered a model for a focal transient perturbation of memory circuits in the temporo-mesial region.
Wolfart S, Quaas AC, Freitag S, Kropp P, Gerber WD, Kern M.
Subjective and objective perception of upper incisors.J Oral Rehabil,
33 (2006), 489-95.
[abstract]
Abstract:
The purpose of this study was to evaluate the subjective judgment (SJ) of patients on their own dental appearance and to correlate the results with objective measurements (OM) of their dentition concerning the appearance of the upper incisors. Seventy-five participants (30 men and 45 women) with normal well-being were included in the study. In a questionnaire they judged the appearance of their upper incisors. Furthermore, OM were evaluated by the investigator with regard to the following points: (i) absolute length of the upper central incisors, (ii) their length exposed during laughing, (iii) width-to-length ratio of central incisors and (iv) the proportion between the width of the lateral and central incisors. The subjective results were registered on visual-analogue scales. For the objective results standardized photographs were taken. No gender dependent differences could be found for the objectively measured parameters (median): OM1, 10.7 mm; OM2, 8.1 mm; OM3, 0.81; OM4, 0.79. However, significant correlations between subjective and objective results (SJ1/OM1, SJ2/OM2, SJ3/OM3) could be shown for men, but not for women. The maximum of the calculated regression-curves for men reflect 'golden standard values' well known from the literature. The degree of satisfaction concerning appearance of anterior incisors in accordance with golden standard values is higher for men than for women.
Wegner PK, Freitag S, Kern M.
Survival rate of endodontically treated teeth with posts after prosthetic restoration.J Endod,
32 (2006), 928-31.
[abstract]
Abstract:
The purpose of this retrospective clinical study was to evaluate the survival rate of teeth that were endodontically treated and restored with endodontic posts and prosthodontic restorations. A total of 864 teeth in 360 patients were included in the study. Dental records and radiographs of the patients were evaluated and four parameters were documented. The parameters were type of post, type of prosthodontic restoration, observation time, and, in cases of failure, failure mode. Statistical survival analyses were performed according to Kaplan-Meier. The mean observation time was 22.5 +/- 14.9 months. The calculated survival rates of the abutments were statistically significant different for fixed partial dentures (FPDs) and for removable partial dentures (RPDs) with survival rates of 92.7% and 51.0% after 60 months, respectively. Most of the presumed factors influencing the survival rate of endodontically treated abutment teeth only affected the outcome in the RPD group. Teeth restored with post and cores present a high risk for failure when used as abutments for conical-double-crown-retained RPDs.
Schafmayer C, Hartleb J, Tepel J, Albers S, Freitag S, Völzke H, Buch S, Seeger M, Timm B, Kremer B, Fölsch UR, Fändrich F, Krawczak M, Schreiber S, Hampe J.
Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany.BMC Gastroenterol,
6 (2006), 36.
[abstract]
Abstract:
BACKGROUND: Gallstones represent a prevalent and costly health problem. The changing epidemiology and the emerging non-surgical interventions for gallstone disease necessitate the definition of target populations for future therapies. This study aimed to define patterns of gallstone composition and identify demographic predictors of gallstone composition in a large sample of symptomatic gallstones from Northern Germany. METHODS: One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry. RESULTS: The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001). CONCLUSION: The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m2 have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones.
Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S, Rehman A, Kühbacher T, Nikolaus S, Namsolleck P, Blaut M, Hampe J, Sahly H, Reinecke A, Haake N, Günther R, Krüger D, Lins M, Herrmann G, Fölsch UR, Simon R, Schreiber S.
Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.Circulation,
113 (2006), 929-37.
[abstract]
Abstract:
Detection of a broad variety of molecular signatures in all CHD specimens suggests that diverse bacterial colonization may be more important than a single pathogen. Our observation does not allow us to conclude that bacteria are the causative agent in the etiopathogenesis of CHD. However, bacterial agents could have secondarily colonized atheromatous lesions and could act as an additional factor accelerating disease progression.
Bolte H, Riedel C, Jahnke T, Inan N, Freitag S, Kohl G, Heller M, Biederer J.
Reproducibility of computer-aided volumetry of artificial small pulmonary nodules in ex vivo porcine lungs.Invest Radiol,
41 (2006), 28-35.
[abstract]
Abstract:
OBJECTIVE: The main purpose of this study was to investigate the reproducibility of computed tomography (CT)-based volumetric measurements of small pulmonary nodules. METHODS: We implanted 70 artificial pulmonary nodules in 5 ex vivo porcine lungs in a dedicated chest phantom. The lungs were scanned 5 times consecutively with multislice-CT (collimation 16 x 0.75 mm, slice thickness 1 mm, reconstruction increment 0.7 mm). A commercial software package was used for lesion volumetry. The authors differentiated between intrascan reproducibility, interscan reproducibility, and results from semiautomatic and postprocessed volumetry. RESULTS: Analysis of intrascan reproducibility revealed a mean variation coefficient of 6.2% for semiautomatic volumetry and of 0.7% for human adapted volumetry. For interscan reproducibility a mean variation coefficient of 9.2% and for human adapted volumetry a mean of 3.7% was detected. CONCLUSION: The presented volumetry software showed a high reproducibility that can be expected to detect nodule growth with a high degree of certainty.
Dümbgen L, Freitag-Wolf S, Jongbloed G.
Estimating a Unimodal Distribution from Interval-Censored Data..Journal of the American Statistical Association,
101 (2006), 1094-1106.
[abstract]
Abstract:
In this paper we consider three nonparametric maximum likelihood estimators based on mixed case interval-censored data. Apart from the unrestricted estimator, we consider estimators under the assumption that the underlying distribution function of event times is concave or unimodal. Characterizations of the estimates are derived, and algorithms are proposed for their computation. The estimators are shown to be asymptotically consistent, and the additional constraints' benefits are illustrated via simulations. Finally, the estimators are used as an ingredient for a nonparametric comparison of two samples.
Attia A, Abdelaziz KM, Freitag S, Kern M.
Fracture load of composite resin and feldspathic all-ceramic CAD/CAM crowns.J Prosthet Dent,
95 (2006), 117-23.
[abstract]
Abstract:
STATEMENT OF PROBLEM: Various machinable materials are currently used with computer-aided design/computer-assisted manufacturing (CAD/CAM) technologies for the chairside fabrication of restorations. However, properties of these new machinable materials, such as fracture load, wear, marginal deterioration, and color stability, should be investigated in vitro under replicated clinical conditions prior to time-consuming clinical studies. PURPOSE: This study investigated the effect of cyclic loading fatigue and different luting agents under wet conditions on the fracture load of CAD/CAM machined composite resin and all-ceramic crowns. MATERIALS AND METHODS: Ninety-six intact human maxillary premolars were prepared for composite resin and all-ceramic crowns with the following preparation criteria: 6-degree axial taper, 1.5-mm shoulder finish line placed 0.5 mm occlusal to the cemento-enamel junction, 1.5-mm axial reduction, 2-mm occlusal reduction, and 5-mm occluso-gingival height. Sixteen unprepared premolars served as controls. Forty-eight all-ceramic crowns (Vita Mark II) and 48 millable composite resin crowns (MZ100 Block) were fabricated using a CAD/CAM system (Cerec 3). Three luting agents-RelyX ARC (RX), GC Fuji CEM (FC), and zinc phosphate cement (ZP)-were used for cementation (n = 16). After 1-week storage in water, half of the specimens (n=8) in each subgroup were cyclically loaded and thermal cycled under wet conditions for 600,000 masticatory cycles and 3500 thermal cycles (58 degrees C/4 degrees C; dwell time, 60 seconds) in a masticatory simulator; the other half (n = 8) were fractured without cyclic loading. All specimens were loaded in a universal testing machine with a compressive load (N) applied along the long axis of the specimen at a crosshead speed of 1 mm/min until fracture. Fracture loads (N) were recorded for each specimen. Three-way analysis of variance was used to detect the effects of the experimental factors (crown material, luting agent, and loading conditions) on the fracture load. The comparison with the unprepared natural teeth as controls was done by means of t tests (alpha=.05). RESULTS: Analysis of variance revealed a statistically significant influence of the luting agent and the cyclic loading (P < .001), whereas the crown material had no significant influence. Cyclic loading fatigue significantly decreased the mean fracture load of test groups independent of the 3 luting agents used: MZ100/ZP, 827.1 to 552.5 N; MZ100/FC, 914.7 to 706.2 N; MZ100/RX, 955.9 to 724.4 N; Vita/ZP, 772.3 to 571.5 N; Vita/FC, 923.6 to 721.1 N; and Vita/RX, 929.1 to 752.7 N. However, there was no significant difference in the mean fracture load of control specimens before and after cyclic loading (1140.1 N and 1066.2 N, respectively). Adhesive luting agents RelyX ARC and GC Fuji CEM increased fracture load significantly compared to zinc phosphate cement. CONCLUSIONS: Cyclic loading fatigue significantly reduced the fracture loads of composite resin and all-ceramic crowns, whereas adhesive cementation significantly increased the fracture loads.
Eberhard J, Reimers N, Dommisch H, Hacker J, Freitag S, Acil Y, Albers HK, Jepsen S.
The effect of the topical administration of bioactive glass on inflammatory markers of human experimental gingivitis.Biomaterials,
26 (2005), 1545-51.
[abstract]
Abstract:
Recent studies demonstrated that bioactive glass attenuated inflammatory reactions and bacterial growth in vitro. The aim of the present clinical study was to evaluate the effects of local bioactive glass-administration in vivo in subjects with experimental gingivitis. In each individual, contralateral teeth served as test and control over a 21-day non-hygiene (preventive phase) and a 7-day therapeutic phase. A 45S5 bioactive glass (10% solution) was applied daily (2 x 1 h) on the test teeth during the preventive and therapeutic phase of the study. Inflammation assessment was based on the plaque index record (PI), on the bleeding frequency (BOP) and the gingival crevicular fluid volume (GCF). Interleukin-1beta levels (IL-1beta) in the GCF were measured by ELISA. Bacterial deposits on teeth increased during the 21-days non-brushing period, with no difference in plaque accumulation between test and control sides. BOP levels were significantly reduced during the therapeutic phase by the application of bioactive glass. GCF-values showed a significant reduction on the test compared to control side during the preventive and therapeutic phase. IL-1beta counts decreased during the last 7 days of the study on the test side, but no significance was given. The topical application of 45S5 bioactive glass in humans with experimental gingivitis attenuated the clinical signs of inflammation, although the bacterial accumulation was not inhibited in this clinical trial.
Quaas AC, Heide S, Freitag S, Kern M.
Influence of metal cleaning methods on the resin bond strength to NiCr alloy.Dent Mater,
21 (2005), 192-200.
[abstract]
Abstract:
OBJECTIVES: The purpose of this laboratory study was to evaluate the influence of different metal cleaning methods on the bond strength of various resin bonding systems and its durability to a NiCr alloy. The hypothesis was that the resin bond strength and its durability is related to the cleaning method and to the bonding system used. METHODS: Plexiglas tubes filled with composite resin were bonded to NiCr disks using three different bonding systems: tribochemical silica-coating and silanization of the alloy, acrylization of the alloy, or bonding with a phosphate monomer containing composite resin. For each bonding system, three cleaning methods were used after the last air abrasion step: cleaning with a stiff brush, ultrasonic cleaning in alcohol or in a neutral detergent. For each combination 20 samples were bonded. Subgroups of 10 bonded samples were tested for tensile strength following storage for either 3 or 150 days. In addition, the 150-day samples were thermal cycled 37,500 times. The statistical analyses were made by ANOVA, followed by multiple pair-wise comparison of the groups using Scheffe and t-tests with Bonferroni-Holm correction. RESULTS: The mean tensile bond strengths ranged from 34.8 to 49.2 MPa after 3 days and from 2.1 to 43.1 MPa after 150 days. Acrylization of the alloy did not provide durable bond strength to NiCr alloy over storage time. Cleaning the alloy surface with alcohol provided statistically significant higher bond strength than the other cleaning methods after 3 days. SIGNIFICANCE: Alloy cleaning methods after air abrasion have a significant influence on the resin bond strength.
Hübner RH, Meffert S, Mundt U, Böttcher H, Freitag S, El Mokhtari NE, Pufe T, Hirt S, Fölsch UR, Bewig B.
Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation.Eur Respir J,
25 (2005), 494-501.
[abstract]
Abstract:
Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio.
Wolfart S, Thormann H, Freitag S, Kern M.
Assessment of dental appearance following changes in incisor proportions.Eur J Oral Sci,
113 (2005), 159-65.
[abstract]
Abstract:
This study aimed to evaluate the assessment of attractiveness of standardized changes in incisor proportions. Two original photographs, showing the maxillary anterior teeth in the frame of a smile, were computer-manipulated. From the so-produced symmetrical 'golden standard' images, two sets were constructed. Each set contained one golden standard image and seven images with different standardized changes concerning (i) width-to-length ratios of the central incisors (60-96%) and (ii) tooth-to-tooth proportions between the widths of lateral and central incisors (43-87%). The judges, consisting of three groups of individuals (24 dentists, 24 medical students, and 179 patients), ranked each photo set for attractiveness on a visual analogue scale. The width-to-length ratios were assessed as most attractive within a range of 75-85% (medical students, patients) or 75-80% (dentists), respectively. The tooth-to-tooth proportions showed the best results concerning attractive appearance within a range of 50-74% (medical students, patients) or 56-68% (dentists), respectively. No significant differences between the participant groups were found except for some extreme variations. It was concluded that a most attractive 'golden range' could be identified for both the width-to-length ratios and the tooth-to-tooth proportions of the maxillary incisors.
Caliebe A, Freitag S, Krawczak M.
Stochastische Modelle für Interaktion und Effektmodifikation.Medizinische genetik,
17 (2005), 14-9.
Domm C, Schünke M, Steinhagen J, Freitag S, Kurz B.
Influence of various alginate brands on the redifferentiation of dedifferentiated bovine articular chondrocytes in alginate bead culture under high and low oxygen tension.Tissue Eng,
10 (2004 Nov-Dec), 1796-805.
[abstract]
Abstract:
We examined the influence of various alginates on the redifferentiation of dedifferentiated articular chondrocytes in alginate bead culture under low (5%) and (21%) high oxygen supply. Isolated bovine articular chondrocytes were dedifferentiated and multiplied by 2-week monolayer culture under 21% oxygen. They were subcultured at a density of 10(7) cells/mL in six different commercially available sodium alginates (1.2%, w/v) and held under 21 or 5% oxygen for 3 weeks. Proliferation (DNA measurement on days 0 and 21 of culture), collagen type II production (immunocytochemistry and Western blotting), and [(3)H]proline and [(35)S]sulfate incorporation were monitored. Collagen type II production was significantly stronger under 5% oxygen compared with 21% oxygen in two alginates (three other alginates nearly reached the significance level). However, alginate-based differences proved not to be significant. [(3)H]Proline incorporation was not influenced by alginate but showed strong oxygen dependency (up to 3-fold higher under 5% oxygen). For [(35)S]sulfate incorporation oxygen dependency was even stronger (up to 8-fold higher under 5% oxygen) and significant alginate-dependent differences were found for several alginates. The effects of the different alginates did not correlate with their pH, viscosity, or guluronic:mannuronic acid ratio. Thus, the type of alginate and even more, the oxygen supply, influence the redifferentiation and matrix production of dedifferentiated bovine articular chondrocytes.
Wolfart S, Brunzel S, Freitag S, Kern M.
Assessment of dental appearance following changes in incisor angulation.Int J Prosthodont,
17 (2004 Mar-Apr), 150-4.
[abstract]
Abstract:
PURPOSE: This study evaluated the assessment of attractiveness of standardized changes in incisor angulation of different tooth arrangements. MATERIALS AND METHODS: Four sets of images showing the maxillary anterior teeth without lips against a black background were used for evaluation. Each set contained the original photograph, one computer-manipulated symmetric image, and four images with different standardized changes in incisor angulation (10 degrees). The judges, consisting of three groups (30 dental students, 30 medical students, 30 art students), ranked each photo set for attractiveness from 1 (most attractive) to 6 (most unattractive). RESULTS: The mean ranking (in parentheses) showed that symmetric teeth with ideal axes (2.5) and changes in the angulation of one (2.8) or both (2.5) lateral incisors were significantly more attractive than the angulation of one (4.2) or both (4.6) central incisors. There were no differences between the groups of participants. All findings were reproducible. CONCLUSION: Tooth arrangements showing central incisors with ideal axes were more attractive. Slight changes in the angulation of one or both lateral incisors did not influence attractiveness negatively.
Habermann JK, Hellman K, Freitag S, Heselmeyer-Haddad K, Hellström AC, Shah K, Auer G, Ried T.
A recurrent gain of chromosome arm 3q in primary squamous carcinoma of the vagina.Cancer Genet Cytogenet,
148 (2004), 7-13.
[abstract]
Abstract:
Primary carcinomas of the vagina are rare tumors, accounting for 2%-3% of all gynecologic malignancies. Only a few karyotypes based on chromosome banding techniques have been reported. We have, therefore, used comparative genomic hybridization to establish a pattern of genomic imbalances in vaginal squamous cell carcinomas. Analysis of 16 formalin-fixed and paraffin-embedded tumors revealed that 70% of vaginal carcinomas carry relative copy number increases that map to chromosome arm 3q. Other recurring gains were observed on chromosome arms 5p and 19p. Chromosomal losses were infrequent. Most tumors were aneuploid, as measured by image cytometry on Feulgen-stained tissue sections. The cytogenetic data were related to the presence of human papillomavirus genomes, expression of laminin-5 as a marker for invasiveness, and expression levels of markers for proliferative activity and mutated TP53. All relevant clinical data were recorded. The results suggest that vaginal carcinomas are defined by a specific distribution of chromosomal aneuploidies and that the pattern of genomic imbalances is strikingly similar to that observed in squamous cell carcinomas of the uterine cervix. Age at diagnosis (P=0.031), tumor size (P=0.025), and increased laminin-5 expression (P=0.006) have a significant influence on the survival time.
Roldán JC, Jepsen S, Miller J, Freitag S, Rueger DC, Açil Y, Terheyden H.
Bone formation in the presence of platelet-rich plasma vs. bone morphogenetic protein-7.Bone,
34 (2004), 80-90.
[abstract]
Abstract:
Growth factors contained in platelet-rich plasma (PRP) have recently been proposed to enhance maturation of bone grafts and, in combination with anorganic bovine bone, to support repair in the treatment of small bone defects in maxillofacial surgery. Bone morphogenetic proteins (BMP) carried in a matrix may be able to replace the autologous bone graft in the treatment of critical size defects. However, no studies have compared the bone stimulating capacity of PRP and BMP. Likewise there is no data comparing the effects of PRP in either an autologous bone graft or in anorganic bovine bone. We augmented the mandible of Wistar rats (n = 28) on both sides with either anorganic bovine bone (Bio-Oss) or autologous rib bone. On the test side we applied either 20 microl of autologous PRP or 10 microl of rhBMP-7 (4 groups, n = 7). In addition, bone induction was evaluated in an extraskeletal site (n = 14). A polychrome sequential labeling was performed. The animals were sacrificed by intra-vital perfusion on day 50. Undecalcified ground sections were evaluated by microradiography, digitized histomorphometry and under fluorescent light. The qualitative analysis of fluorochrome labels suggested that PRP and rhBMP-7 accelerated bone growth. However, histomorphometric analysis revealed no significant differences in the area of newly mineralized bone under either the influence of PRP or rhBMP-7 on autologous bone graft. Likewise, the addition of PRP to anorganic bovine bone showed no statistical difference to the control group. The strongest bone stimulating effect was seen for the combination of rhBMP-7 with anorganic bovine bone (p = 0.028). In the extraskeletal model, newly formed bone was evident in the presence of rhBMP-7, but not of PRP. In conclusion, according to the histomorphometry, the addition of platelet-rich plasma failed to enhance bone formation on anorganic bovine bone and on autologous bone grafts.
Böning A, Scheewe J, Ivers T, Friedrich C, Stieh J, Freitag S, Cremer JT.
Phosphorylcholine or heparin coating for pediatric extracorporeal circulation causes similar biologic effects in neonates and infants.J Thorac Cardiovasc Surg,
127 (2004), 1458-65.
[abstract]
Abstract:
OBJECTIVE: Cardiac surgery for complex congenital malformations with use of extracorporeal circulation predisposes to an excessive systemic inflammatory response and a consecutive capillary leak syndrome. In a prospective randomized study the influence of 2 oxygenators especially designed for pediatric use on inflammatory markers and clinical outcome was investigated. METHODS: Forty neonates and infants (body surface area, <0.36 m(2)) undergoing cardiac surgery with extracorporeal circulation were randomized into one of 3 groups: in the first group (n = 14) the Medtronic Minimax Oxygenator and in the second group (n = 12) the Dideco Lilliput 1 Oxygenator, both with a 750-mL priming volume, were used. In the third group the Dideco Lilliput 1 Oxygenator was filled with a reduced priming volume of 450 mL. Parameters of interest for evaluation of a systemic inflammatory response after extracorporeal circulation were interleukin 6, tumor necrosis factor alpha, neutrophil elastase, complement C3, and free hemoglobin. In addition, erythrocyte, leukocyte, and thrombocyte counts and hemoglobin and C-reactive protein values were determined at different measurement points before, during, and after the operation. RESULTS: In all 3 groups peak values for tumor necrosis factor alpha were observed during the operation, whereas interleukin 6, elastase, and free hemoglobin values peaked in the first 4 hours. The highest values for leukocytes and C-reactive protein were obtained between 24 and 72 hours after the operation. Erythrocyte and thrombocyte counts, as well as hemoglobin values, were lowest at extracorporeal circulation onset, normalizing under substitution in the first 4 hours after the operation. By using the Lilliput/750 oxygenator, higher interleukin 6 values 1 and 4 hours after the operation and higher tumor necrosis factor alpha values during and 1 hour after the operation could be observed compared with results with the Minimax and Lilliput/450 oxygenators. In spite of our randomization protocol, patients in the Lilliput/750 group were significantly smaller and younger than those in the Minimax group. However, the statistical analysis showed no correlation between age and interleukin 6 or tumor necrosis factor alpha values, but it did show a correlation between younger age and the occurrence of capillary leak syndrome. Accordingly, the number of children with clinically complicated course (capillary leak, longer duration of catecholamine therapy, and ventilation) was higher in the Lilliput/750 group than in the Minimax group. CONCLUSION: By using an adequate priming volume, the systemic inflammatory response is similar after use of the Dideco Lilliput 1 Oxygenator and the Medtronic Minimax Oxygenator. Tip-to-tip surface coating of the extracorporeal circulation with either heparin or phosphorylcholine seems to have similar biologic effects in neonates and infants undergoing cardiac surgery.
Eberhard J, Damm S, Freitag S, Albers HK, Jepsen S.
Plaque removing capacity of a novel high pressure water irrigator.Am J Dent,
17 (2004), 199-202.
[abstract]
Abstract:
PURPOSE: To evaluate the capacity of a novel oral water irrigator to remove established plaque deposits. METHODS: The study was designed as a randomized two-treatment, crossover, examiner-blinded clinical trial. The plaque removing capability of a prototype oral irrigator was compared to a conventional electric toothbrush. After 48 hours of plaque accumulation the 35 subjects were randomly assigned to professional plaque removal by either oral irrigation or by electric toothbrushing for a timed 2-minute total cleaning. Pre- and post cleaning plaque was disclosed and gingival abrasions were identified. Plaque was assessed on gingival and approximal surfaces of the oral and buccal sites according to the Rustogi et al modification of the Modified Navy Plaque Index. The assessment of gingival abrasions was performed according to the method introduced by Danser et al. RESULTS: The overall plaque removing capacity of the oral irrigator reached approximately 40.7 +/- 16.7% as compared to 71.6 +/- 11.5% by the electric toothbrush. Similar effects were observed for the gingival and approximal areas. The electric toothbrush caused significantly more gingival abrasions than the oral irrigator.
Dümbgen L, Freitag S, Jongbloed G.
Consistency of Concave Regression with an Application to Current-Status Data.Mathematical Methods of Statistics,
(2004), 69-81.
[abstract]
Abstract:
We consider the problem of nonparametric estimation of a concave regression function F. We show that the supremum distance between the least squares estimator and F on a compact interval is typically of order (log(n)/n)2/5. This entails rates of convergence for the estimator's derivative. Moreover, we discuss the impact of additional constraints on F such as monotonicity and pointwise bounds. Then we apply these results to the analysis of current status data, where the distribution function of the event times is assumed to be concave.
Biederer J, Schoene A, Freitag S, Reuter M, Heller M.
Simulated pulmonary nodules implanted in a dedicated porcine chest phantom: sensitivity of MR imaging for detection.Radiology,
227 (2003), 475-83.
[abstract]
Abstract:
PURPOSE: To evaluate the diagnostic accuracy of common magnetic resonance (MR) imaging sequences for detection of small pulmonary nodules by using a chest phantom and porcine lungs containing simulated lesions. MATERIALS AND METHODS: Fourteen porcine lungs containing 366 porcine myocardial tissue implants were inflated inside a phantom. Two-dimensional (2D) and three-dimensional (3D) gradient-echo (GRE), T2-weighted turbo spin-echo (SE), and T2-weighted single-shot SE train MR sequences were performed. Spiral computed tomography (CT) was performed for comparison. Blinded observers read the images and recorded the sizes and locations of visible nodules by consensus. The sensitivity of each imaging method for depicting single nodules of given sizes was calculated. Specificities, positive predictive values (PPVs), and negative predictive values (NPVs) for detection of one or more nodules of various sizes were calculated. RESULTS: Sensitivities of 3D GRE, 2D GRE, T2-weighted turbo SE, and T2-weighted single-shot SE train MR imaging and of CT were 0.50, 0.40, 0.12, 0.00, and 0.55, respectively, for detection of 1.4-mm nodules and 0.88, 0.84, 0.69, 0.06, and 0.96, respectively, for detection of 4.2-mm nodules. The 95% CIs for CT and GRE MR imaging overlapped, but those for turbo SE and single-shot SE train MR imaging differed significantly (P <.05). For detection of nodules larger than 5 mm, all examinations except single-shot SE train MR imaging yielded a specificity, PPV, and NPV of 1.00 each. For detection of nodules smaller than 5 mm, diagnostic accuracy of 3D GRE MR imaging was high: Specificity, PPV, and NPV all were approximately 0.90. Two-dimensional GRE MR imaging results were influenced by false-positive findings: Specificity was 0.64; PPV, 0.74; and NPV, 1.00. CONCLUSION: Common MR imaging sequences such as 3D GRE have high diagnostic accuracy in depicting small pulmonary nodules when artifacts from cardiac and respiratory motion are absent.
Habermann JK, Upender MB, Roblick UJ, Krüger S, Freitag S, Blegen H, Bruch HP, Schimmelpenning H, Auer G, Ried T.
Pronounced chromosomal instability and multiple gene amplifications characterize ulcerative colitis-associated colorectal carcinomas.Cancer Genet Cytogenet,
147 (2003), 9-17.
[abstract]
Abstract:
Patients with ulcerative colitis have a significantly increased lifetime risk for the development of colorectal carcinomas. While genetic and genomic changes during carcinogenesis have been thoroughly studied in sporadic colorectal cancers, less is known about ulcerative colitis-associated colorectal carcinomas. The aim of this study was to extend the identification of specific genomic imbalances to ulcerative colitis-associated colorectal carcinomas and to establish a comprehensive map of DNA gains and losses by investigating 23 tumor specimens from 23 patients. The molecular cytogenetic characterization was performed using comparative genomic hybridization; immunohistochemistry was used to measure proliferative activity and laminin-5 expression as a marker for invasiveness. The results indicate that these tumors are invariably aneuploid, with a high proliferative activity and increased invasive potential. The average number of copy alterations correlates with increased cyclin A levels (P=0.044), which is an independent predictor of risk of carcinoma development in ulcerative colitis. Despite severe genetic instability, the general pattern of specific chromosomal aberrations that defines sporadic colorectal carcinomas is maintained in ulcerative colitis-associated malignancies. High-level copy number increases (amplifications) are dispersed throughout the genome. Strikingly, these amplifications are much more frequent than in sporadic carcinomas and map to chromosomal regions that have not been described before.
Biederer J, Busse I, Grimm J, Reuter M, Muhle C, Freitag S, Heller M.
[Sensitivity of MRI in detecting alveolar Infiltrates: Experimental studies].Rofo,
174 (2002), 1033-9.
[abstract]
Abstract:
PURPOSE: An experimental study using porcine lung explants and a dedicated chest phantom to evaluate the signal intensity of artificial alveolar infiltrates with T 1 - and T 2 -weighted MRI sequences. MATERIAL AND METHODS: 10 porcine lung explants were intubated, transferred into the cavity of a MRI-compatible chest phantom and inflated by continuous evacuation of the artificial pleural space. All lungs were examined with MRI at 1.5 T before and after intra-tracheal instillation of either 100 or 200 ml gelatine-stabilised liquid to simulate alveolar infiltrates. MR-examination comprised gradient echo (2D- and 3D-GRE) and fast spin echo sequences (T 2 -TSE and T 2 -HASTE). The signal intensity of lung parenchyma was evaluated at representative cross sections using a standardised scheme. Control studies were acquired with helical CT. RESULTS: The instilled liquid caused patchy confluent alveolar infiltrates resembling the findings in patients with pneumonia or ARDS. CT revealed typical ground-glass opacities. Before the application of the liquid, only T 2 -HASTE and T 2 -TSE displayed lung parenchyma signals with a signal/noise ratio of 3.62 and 1.39, respectively. After application of the liquid, both T 2 -weighted sequences showed clearly visible infiltrates with an increase in signal intensity of approx. 30 % at 100 ml (p < 0.01) and 60 % at 200 ml (p < 0.01). With 2D- and 3D-GRE the infiltrates were not visible, although the lung parenchyma signal increase was statistically significant. On 2D-GRE the increase in signal intensity reached 0.74 % (p = 0.32) after 100 ml and 5.6 % (p < 0.01) after 200 ml (for 3D-GRE: 2.2 % [p = 0.02] at 100 ml and 4.4 % at 200 ml [p < 0.01]). The CT controls revealed a significant increase of lung density of 17 H.E. at 100 ml (p = 0.02) and 75 H.E. at 200 ml (p < 0.01). CONCLUSIONS: MRI with T 2 -weighted sequences detects artificial alveolar infiltrates with high signal intensity and may be a highly sensitive tool to detect pneumonia in patients.
Habermann J, Lenander C, Roblick UJ, Krüger S, Ludwig D, Alaiya A, Freitag S, Dümbgen L, Bruch HP, Stange E, Salo S, Tryggvason K, Auer G, Schimmelpenning H.
Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment.Scand J Gastroenterol,
36 (2001), 751-8.
[abstract]
Abstract:
BACKGROUND: Ulcerative colitis patients are at increased risk for developing colorectal carcinomas. Despite expensive surveillance programmes, clinical practice reflects an uncertainty in individual risk assessment. The aim of the study was to evaluate independent cellular features with possible predictive value. METHODS: Two patient groups were selected: group A comprised 8 patients with ulcerative colitis-associated colorectal carcinomas, group B comprised 16 ulcerative colitis patients with risk factors (duration of disease, extent of inflammation, epithelial dysplasias). A total of 683 paraffin-embedded mucosal biopsies were retrospectively evaluated for inflammatory activity, grade of dysplasia, ploidy status, laminin-5 gamma2 chain and cyclin A expression. RESULTS: Mild or moderate inflammatory activity was present in 78% of all biopsies, low- or high-grade dysplasia in 5.5%. There was no difference in inflammatory activity and dysplasia between patient groups. In group A, 75% of the biopsies exhibited aneuploid DNA distribution patterns. Group B showed mainly proliferative-diploid cell populations (85% / P = 0.006). Laminin-5 gamma2 chain was expressed in 13% of all biopsies, with a higher frequency in group A (P = 0.002). Cyclin A expression was found in 98% of all biopsies, with a higher number of immunopositive cells in group A biopsies (P = 0.014). CONCLUSIONS: Combined nuclear DNA assessment, laminin-5 gamma2 chain and cyclin A expression may help to identify ulcerative colitis patients with an increased risk for cancer development.
