Biomedical subjects

Christoph Becker

Publications and source records attributed to Christoph Becker.

At least 19 recordsLinked to original sources

PubMed2007

Different types of scaffolds for reconstruction of the urinary tract by tissue engineering.

INTRODUCTION: Tissue engineering is an important and expanding field in reconstructive surgery. The ideal biomaterial for urologic tissue engineering should be biodegradable and support autologous cell growth. We examined different scaffolds to select the ideal material for the reconstruction of the bladder wall by tissue engineering. MATERIALS AND METHODS: We seeded mouse fibroblasts and human keratinocytes in a co-culture model on 13 different scaffolds. The cell-seeded scaffolds were fixed and processed for electron microscopy, hematoxylin and eosin stain, and immunohistochemistry. Cell density and epithelial cell layers were evaluated utilizing a computer-assisted optical measurement system. RESULTS: Depending on the growth pattern, scaffolds were classified into the following three distinct scaffold types: carrier-type scaffolds with very small pore sizes and no ingrowth of the cells. This scaffold type induces a well-differentiated epithelium. Fleece-type scaffolds with fibers and huge pores. We found cellular growth inside the scaffold but no epithelium on top of it. Sponge-type scaffolds with pores between 20 and 40 microm. Cellular growth was observed inside the scaffold and well-differentiated epithelium on top of it. CONCLUSION: To our knowledge, this is the first time three distinct scaffold types have been reported. All types supported the cell growth. The structure of the scaffolds affects the pattern of cell growth.

Absorbable Implants↗

PubMed2006

Biomechanical evaluation of different fixation methods for tibial eminence fractures.

BACKGROUND: Tibial eminence fractures have become more common, but the best method of fixing these fractures arthroscopically has not been elucidated. OBJECTIVE: The objective of this study is to assess the stability of different fixation methods for tibial eminence fractures. STUDY DESIGN: Controlled laboratory study. METHODS: The authors evaluated the initial fixation strength of 4 different fixation techniques for tibial eminence fractures (2 screws, 1 screw, suture fixation with 1 mm Ethibond, and suture fixation with No. 5 FiberWire) using single cycle and cyclic loading tests. The tests were performed by loading the knee with an anterior tibial shear force. RESULTS: Suture cerclage with the FiberWire showed significantly higher maximum load (599.6 N) and stiffness (36.99 N/mm) than all other fixation methods tested. The lowest maximum load in the single cycle loading test was observed in the group with 2 screws (1 screw, 371.2 N; 2 screws, 249.8 N). The lowest stiffness was found in the Ethibond group (14.5 N/mm). After 1000 cycles of loading, the maximum load of the FiberWire fixation was significantly higher than the maximum load of the Ethibond fixation (399.4 N), the fixation with 1 screw (354.2 N), and the fixation with 2 screws (301.5 N). CONCLUSION: These biomechanical data suggest that under cyclic loading conditions, suture fixation of tibial eminence fractures provides more fixation strength than screw fixation. CLINICAL RELEVANCE: A second screw has no positive effect on the biomechanical characteristics of screw fixation.

Animals↗

PubMed2006

Multislice computed tomography for determination of coronary artery disease in a symptomatic patient population.

BACKGROUND: Multislice computed tomography (MSCT) has started to replace Electron beam CT for quantitation of coronary artery calcium. However no study has evaluated the diagnostic accuracy of MSCT for prediction of coronary artery disease (CAD) in a symptomatic patient population using the volume score. METHODS AND RESULTS: 1347 symptomatic subjects (male = 803, mean age = 62 years) with suspected CAD underwent MSCT studies 1 +/- 2 days before the coronary angiogram. The Agatston (ACS) and Volumetric calcium score (VCS) were calculated using a proprietary workstation. Statistical analyses included the Pearson's correlation coefficient and the nonparametric Mann-Whitney U-test to compare the calcium score in different age groups and between men and women. Sensitivity, specificity and predictive accuracy were calculated for different calcium thresholds for prediction of CAD. ROC curve analyses were used to establish relations between the coronary calcium score and presence or absence of CAD. In 720 (53%) subjects (male = 419) angiography revealed a minimal lumen diameter stenosis greater than 50%. Patients with significant CAD had significantly higher total calcium score values than patients without CAD (P = 0.001). ACS and VCS demonstrate a close correlation for the whole study group, r = 0.99. The overall sensitivity of any calcium to predict stenosis was 99%, specificity = 32%. Exclusion of calcium was highly accurate for exclusion of CAD in subjects older than 50 years (predictive accuracy = 98%). An absolute cutoff >100 and an age and sex specific threshold (score over 75th percentile) were identified as the cutoff levels with the highest sensitivities (86-89%) and lowest false positive rates (20-22%). ROC analyses revealed MSCT calcium scanning as a good clinical test which can be performed with similar accuracy in all age groups with an area under the curve of 0.84. CONCLUSION: Determination of coronary calcium with MSCT is an accurate imaging modality for prediction of significant CAD in a patient population with intermediate likelihood of CAD. Exclusion of any calcium provided strong evidence that patients older than 50 years did not have obstructive CAD. ACS and VCS show an equivalent diagnostic accuracy.

Area Under Curve↗

PubMed2006

Sixty-four slice spiral CT angiography does not predict the functional relevance of coronary artery stenoses in patients with stable angina.

PURPOSE: The aim of this study was to evaluate spiral multidetector computed tomography (MDCT) angiography using 64-slice technique in the detection of functionally relevant coronary artery stenoses (CAS). METHODS: Thirty-eight patients (62+/-11 years, 28 men) with stable angina (26 with suspected and 12 with known coronary artery disease) were investigated using 64-slice MDCT angiography and gated myocardial perfusion SPECT (gated SPECT); a subgroup of 30 patients had additional invasive coronary angiography (ICA). Stenoses with luminal narrowing of >or=50% were defined as "significant" in MDCT angiography and ICA. MDCT angiography was compared with gated SPECT and the combination of gated SPECT plus ICA with respect to the detection of functionally relevant CAS. RESULTS: The sensitivity, specificity and negative and positive predictive values of MDCT angiography in detecting reversible perfusion defects on gated SPECT were 63%, 80%, 94% and 32%, respectively, in vessel-based analysis and 71%, 62%, 72% and 60%, respectively, in patient-based analysis. If only reversible perfusion defects on gated SPECT with CAS >or=50% on ICA were considered, the sensitivity, specificity and negative and positive predictive values were, respectively, 85%, 79%, 98% and 33% for vessel-based analysis and 85%, 59%, 83% and 61% for patient-based analysis. CONCLUSION: Sixty-four slice MDCT angiography failed to predict the functional relevance of CAS, but had a high negative predictive value in the exclusion of functionally relevant CAS in symptomatic patients.

Angina Pectoris↗

PubMed2006

Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis.

Although IL-12 and IL-23 share the common p40 subunit, IL-23, rather than IL-12, seems to drive the pathogenesis of experimental autoimmune encephalomyelitis and arthritis, because IL-23/p19 knockout mice are protected from disease. In contrast, we describe in this study that newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19-deficient mice produce elevated levels of IL-12, and that IL-23 down-regulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23-deficient mice rescued mice from lethal colitis. Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis.

Animals↗

PubMed2006

Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins.

We have shown recently that the azathioprine metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes. In the present study, we describe a new molecular mechanism by which 6-Thio-GTP blocks GTPase activation. Although 6-Thio-GTP could bind to various small GTPases, it specifically blocked activation of Rac1 and Rac2 but not of closely related Rho family members such as Cdc42 and RhoA in primary T cells upon stimulation with alphaCD28 or fibronectin. Binding of 6-Thio-GTP to Rac1 did not suppress Rac effector coupling directly but blocked Vav1 exchange activity upon 6-Thio-GTP hydrolysis, suggesting that 6-Thio-GTP loading leads to accumulation of 6-Thio-GDP-loaded, inactive Rac proteins over time by inhibiting Vav activity. In the absence of apoptosis, blockade of Vav-mediated Rac1 activation led to a blockade of ezrin-radixin-moesin dephosphorylation in primary T cells and suppression of T cell-APC conjugation. Azathioprine-generated 6-Thio-GTP thus prevents the development of an effective immune response via blockade of Vav activity on Rac proteins. These findings provide novel insights into the immunosuppressive effects of azathioprine and suggest that antagonists of the Vav-Rac signaling pathway may be useful for suppression of T cell-dependent pathogenic immune responses.

Adult↗

PubMed2006

Drug insight: novel small molecules and drugs for immunosuppression.

Gastrointestinal diseases can result from the inadequate or excessive response of the immune system to self or innocuous antigens. Moreover, the physiologic activation of the immune system against non-self antigens is a major clinical problem in liver organ transplantation. At present, many drugs are available that suppress the activation of the immune system, although most of the currently used immunosuppressive drugs lack specificity in terms of their molecular targets and, therefore, have the potential to generate numerous side effects. The advances that have been made in understanding the molecular events that underlie the activation of the immune system have led to the development of a new generation of 'small molecules' that are endowed with immunosuppressive properties and can serve as immunomodulatory agents. Among these new small molecules, inhibitors of Janus kinase 3, p21-Rac1 and p38 mitogen-activated protein kinase represent the most innovative approach to immunosuppression, and could be a promising alternative to current immunosuppressive therapies. Here, we report on the progress that has been made in the development of small molecules in the field of gastroenterology.

Animals↗

PubMed2006

Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.

BACKGROUND: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb). METHODS: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported. RESULTS: To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-gamma. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-gamma and tumor necrosis factor-alpha secretion. CONCLUSIONS: We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb.

Adolescent↗

PubMed2005

First performance evaluation of a dual-source CT (DSCT) system.

We present a performance evaluation of a recently introduced dual-source computed tomography (DSCT) system equipped with two X-ray tubes and two corresponding detectors, mounted onto the rotating gantry with an angular offset of 90 degrees . We introduce the system concept and derive its consequences and potential benefits for electrocardiograph [corrected] (ECG)-controlled cardiac CT and for general radiology applications. We evaluate both temporal and spatial resolution by means of phantom scans. We present first patient scans to illustrate the performance of DSCT for ECG-gated cardiac imaging, and we demonstrate first results using a dual-energy acquisition mode. Using ECG-gated single-segment reconstruction, the DSCT system provides 83 ms temporal resolution independent of the patient's heart rate for coronary CT angiography (CTA) and evaluation of basic functional parameters. With dual-segment reconstruction, the mean temporal resolution is 60 ms (minimum temporal resolution 42 ms) for advanced functional evaluation. The z-flying focal spot technique implemented in the evaluated DSCT system allows 0.4 mm cylinders to be resolved at all heart rates. First clinical experience shows a considerably increased robustness for the imaging of patients with high heart rates. As a potential application of the dual-energy acquisition mode, the automatic separation of bones and iodine-filled vessels is demonstrated.

Coronary Angiography↗

PubMed2005

TGF-beta as a T cell regulator in colitis and colon cancer.

TGF-beta is a pleiotropic cytokine with powerful immunosuppressive functions. Mice deficient for TGF-beta1 show a dramatic phenotype with severe multiorgan inflammation and die shortly after birth. Recent investigations have highlighted the role of TGF-beta in suppression of T cell mediated autoimmune inflammation and anti-tumor immunity. In addition to its direct anti-inflammatory effects on T cells, TGF-beta has been implicated as central regulator of regulatory T cells. TGF-beta not only mediates the suppression of effector T cells by Tregs, recent evidence also reveals a role for TGF-beta along with TCR stimulation in the peripheral induction of regulatory T cells from naïve CD4+CD25- cells.

Animals↗

PubMed2005

EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-kappa B activation.

The EBV-induced gene 3 (EBI3) is expressed in dendritic cells (DCs) and part of the cytokine IL-27 that controls Th cell development. However, its regulated expression in DCs is poorly understood. In the present study we demonstrate that EBI3 is expressed in splenic CD8(-), CD8(+), and plasmacytoid DC subsets and is induced upon TLR signaling. Cloning and functional analysis of the EBI3 promoter using in vivo footprinting and mutagenesis showed that stimulation via TLR2, TLR4, and TLR9 transactivated the promoter in primary DCs via NF-kappaB and Ets binding sites at -90 and -73 bp upstream of the transcriptional start site, respectively. Furthermore, we observed that NF-kappaB p50/p65 and PU.1 were sufficient to transactivate the EBI3 promoter in EBI3-deficient 293 cells. Finally, induced EBI3 gene expression in DCs was reduced or abrogated in TLR-2/TLR4, TLR9, and MyD88 knockout mice, whereas both basal and inducible EBI3 mRNA levels in DCs were strongly suppressed in NF-kappaB p50-deficient mice. In summary, these data suggest that EBI3 expression in DCs is transcriptionally regulated by TLR signaling via MyD88 and NF-kappaB. Thus, EBI3 gene transcription in DCs is induced rapidly by TLR signaling during innate immune responses preceding cytokine driven Th cell development.

Animals↗

PubMed2005

Visualising noncalcified coronary plaques by CT.

Due to a rapid improvement of the new generation submillimetre multislice CT-technology noninvasive tomographic imaging of the coronary vessel wall has become reality. First clinical studies have shown the ability in particular of 16-slice CT to determine plaque burden, plaque composition and compensatory vessel-wall remodelling. These novel findings already constitute an important step forward to assess coronary atherosclerosis noninvasively in a detailed manner which opens promising new opportunities for a better understanding and riskstratification of coronary atherosclerosis. Current limitations, mainly the insufficient accuracy to detect small lesions in distal coronary segments, might be overcome by improved spatial and temporal resolution of the new generation scanners operating with 64 and more detectors.

Contrast Media↗

PubMed2005

Stepwise regulation of TH1 responses in autoimmunity: IL-12-related cytokines and their receptors.

Interleukin (IL)-12 is a key cytokine of cell-mediated immune responses. Until recently, IL-12 was believed to be unique in its ability to induce the differentiation of naive T cells toward the TH1 phenotype and in its pathogenic activity, as shown in various disease models including inflammatory bowel disease. However, recently, 2 additional cytokines closely related to IL-12, IL-23 and IL-27, were discovered. Until then, the role of IL-12 was overestimated because it was believed that the p40 subunit was unique to IL-12. The discovery that IL-12 shares p40 with IL-23 and that IL-23 but not IL-12 is essential in models of chronic inflammation and autoimmunity led to a model in which IL-12 is essential to induce interferon-gamma-producing TH1 cells, whereas IL-23 mediates effector functions. The latest cytokine added to this cytokine family is IL-27. IL-27 has the unique feature to act on naive T cells, rendering them susceptible to IL-12 signaling. Thus, IL-27 may be essential for the early events of a cell-mediated immune response. This review focuses on these novel cytokines and their role in cell-mediated immune responses and discusses differences and common features within the family of IL-12-related cytokines.

Animals↗

PubMed2005

Angiogenesis, immune system and growth factors: new targets in colorectal cancer therapy.

Colorectal cancer is the second most common malignant human neoplasia. Over recent years, many efforts have been performed in order to develop and improve therapeutic protocols, and many advances have been accomplished in both the field of adjuvant and palliative therapy. Most of the chemotherapic agents currently used in the clinical setting are the products of decades of research aimed at inhibiting the uncontrolled growth of dysplastic cells. However, new frontiers in this field have recently been opened, with the identification of key molecules involved in physiologic mechanisms that are of fundamental importance for cancer development and progression. Tumor-induced angiogenesis, the cancer-immune system crosstalk and the effect of growth factors on dysplastic cells represent new fields of investigation for anticancer therapy.

Angiogenesis Inhibitors↗

PubMed2005

Comparison of spiral multidetector CT angiography and myocardial perfusion imaging in the noninvasive detection of functionally relevant coronary artery lesions: first clinical experiences.

UNLABELLED: Compared with conventional coronary angiography, spiral multidetector CT (MDCT) angiography has delivered promising accuracy in the detection and validation of coronary lesions. Myocardial perfusion imaging (MPI) using SPECT is an established method for noninvasively assessing the functional significance of coronary stenoses and delivers valuable information for risk stratification. This retrospective analysis compared the accuracies of MDCT angiography and MPI in the detection of hemodynamically relevant lesions of the coronary arteries. METHODS: Twenty-five patients with suspected or known coronary artery disease were studied. Electrocardiographically gated MPI and 16-MDCT angiography were performed. Myocardial perfusion images were analyzed by 2 experienced observers, and reversible and fixed perfusion defects were detected and allocated to their corresponding coronary vessels. For the evaluation of MDCT angiography, image quality was determined, and lesions > or = 50% and luminal narrowing < 50% were visually assessed and characterized by 2 independent observers unaware of the results of MPI. RESULTS: Ninety-nine coronary vessels were analyzed, and the quality of MDCT angiography images was assessed for 330 coronary segments. Coronary artery diameter was interpretable for 231 (70%) of 330 segments, whereas in 99 (30%) of 330 segments, vessel diameter could not be evaluated because of heavy calcifications, blurring, motion artifacts, or intracoronary stents. MDCT angiography detected stenoses > or = 50% in 15 of 100 coronary arteries. Eight (53%) of 15 stenoses > or = 50% showed reversible or fixed perfusion defects in the corresponding myocardial areas on MPI. Sensitivity, specificity, and negative and positive predictive values were 100%, 87%, 100%, and 29%, respectively, for the ability of MDCT angiography to detect reversible perfusion defects in the corresponding myocardial areas. CONCLUSION: MDCT angiography detected myocardial ischemia, as defined by reversible perfusion defects on MPI, with a positive predictive value of 29% in a nonselected study cohort. Compared with MPI alone, MDCT angiography added important morphologic information, but MPI remains mandatory for evaluating the functional relevance of coronary artery lesions.

Coronary Angiography↗

PubMed2004

Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells.

Data regarding the role of TGF-beta for the in vivo function of regulatory CD4(+)CD25(+) T cells (Treg) are controversial. A transgenic mouse model with impaired TGF-beta signaling specifically in T cells was used to assess the role of endogenous TGF-beta for the in vivo function of CD4(+)CD25(+) Treg in a murine model of colitis induced by dextran sulfate. Transfer of wild-type, but not transgenic CD4(+)CD25(+) Treg was found to suppress colitis in wild-type mice. In addition, by transferring CFSE-labeled CD4(+)CD25(+) Treg we could demonstrate that endogenous TGF-beta promotes the expansion of CD4(+)CD25(+) Treg in vivo. Transgenic mice themselves developed reduced numbers of peripheral CD4(+)CD25(+) Treg and were more susceptible to the induction of colitis, which could be prevented by the transfer of wild-type Treg. These data indicate that TGF-beta signaling in CD4(+)CD25(+) Treg is required for their in vivo expansion and suppressive capacity.

Adoptive Transfer↗

PubMed2004

A critical regulatory role of leucin zipper transcription factor c-Maf in Th1-mediated experimental colitis.

In this study, we investigated the role of c-Maf, a transcription factor known to induce IL-4 production, in inflammatory bowel diseases and experimental colitis. Although Crohn's disease (CD) is associated with low IL-4 production by T-bet-expressing Th1 cells in the lamina propria, surprisingly a higher expression of c-Maf in these cells was found as compared with control patients. The relevance of this finding was further evaluated in an animal model of CD induced by adoptive transfer of CD4(+)CD62L(+) T cells in RAG-deficient mice. In this Th1-mediated model, an increase of c-Maf-expressing T lymphocytes in the lamina propria over time was observed. Interestingly, adoptive transfer of c-Maf transgenic CD4(+)CD62L(+) T cells in RAG-1-deficient mice resulted in an IL-4-dependent inability to induce colitis and suppressed colitis activity induced by wild-type CD4(+)CD62L(+) T cells. In contrast, transfer of CD4(+)CD62L(-) T cells from c-Maf transgenic, but not wild-type mice induced colitis and augmented colitis induced by CD4(+)CD62L(+) T cells from wild-type mice in an IL-4-independent pathway, as determined by macroscopic, histologic, and endoscopic criteria. This was associated with an accumulation of CD4(+) T-bet(+) CD25(+) effector Th1 cells in the lamina propria of colitic mice. Our results reveal a novel regulatory role of c-Maf in colitis. Although overexpression of c-Maf in naive T cells prevents Th1-mediated colitis, overexpression of c-Maf in memory T-bet(+) Th1 cells regulates CD25 expression and augments such colitis. Targeting of c-Maf in memory T cells in CD appears to be an attractive target for therapeutic interventions.

Animals↗

PubMed2004

Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7.

CD4(+)CD25(+) regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-beta is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4(+)CD25(-) peripheral murine T cells. Similarly, TGF-beta induced Foxp3 in human CD4(+)CD25(-) T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-beta and limits TGF-beta signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4(+)CD25(-) T cells highly susceptible to the morphogenic and regulatory effects of TGF-beta signaling via Smad3/4. In summary, we demonstrate that TGF-beta induces a regulatory phenotype in CD4(+)CD25(-) T cells through the induction of Foxp3 and a positive autoregulatory loop of TGF-beta signaling due to the absence of Smad7.

Animals↗