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Christoph Becker

Publications and source records attributed to Christoph Becker.

At least 37 records · Page 2Linked to original sources
PubMed2004

Accuracy of multidetector spiral computed tomography in identifying and differentiating the composition of coronary atherosclerotic plaques: a comparative study with intracoronary ultrasound.

OBJECTIVES: We evaluated the accuracy of contrast-enhanced multidetector spiral computed tomography (MDCT) for the noninvasive detection and classification of coronary plaques and compared it with intracoronary ultrasound (ICUS). BACKGROUND: Noninvasive determination of plaque composition and plaque burden may be important to improve risk stratification and to monitor progression of coronary atherosclerosis. METHODS: We included 46 consecutive patients with a distinctive risk profile, who were investigated by ICUS (Goldvision, 20 MHz, Jomed Inc., Rancho Cordova, California). Due to the inability to slow the heart rate below 65 beats/min (n = 7) and due to renal insufficiency (n = 2), nine of 46 consecutive patients could not be studied by MDCT (Sensation 16, Siemens, Forchheim, Germany). RESULTS: In the remaining 37 patients, 68 vessels were investigated by ICUS, and 58 of these vessels were visualized by MDCT with image quality sufficient for analysis. In these vessels that were divided in 3-mm sections, MDCT correctly classified 62 of 80 (78%) sections containing hypoechoic plaque areas, 87 of 112 (78%) sections containing hyperechoic plaque areas, and 150 of 158 (95%) sections containing calcified plaque tissue. In 484 of 525 (92%) sections, atherosclerotic lesions were correctly excluded. The MDCT-derived density measurements within coronary lesions revealed significantly different values for hypoechoic (49 HU [Hounsfield Units] +/- 22), hyperechoic (91 HU +/- 22), and calcified plaques (391 HU +/- 156, p < 0.02). CONCLUSIONS: This study demonstrates that, in the case of diagnostic image quality, contrast-enhanced MDCT permits an accurate identification of coronary plaques and that computed tomography density values measured within plaques reflect echogenity and plaque composition.

Aged↗
PubMed2004

Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors.

Meprin is a zinc endopeptidase of the astacin family, which is expressed as a membrane-bound or secreted protein in mammalian epithelial cells, in intestinal leucocytes and in certain cancer cells. There are two types of meprin subunits, alpha and beta, which form disulphide-bonded homo- and hetero-oligomers. Here we report on the cleavage of matrix proteins by hmeprin (human meprin) alpha and beta homo-oligomers, and on the interactions of these enzymes with inhibitors. Despite their completely different cleavage specificities, both hmeprin alpha and beta are able to hydrolyse basement membrane components such as collagen IV, nidogen-1 and fibronectin. However, they are inactive against intact collagen I. Hence the matrix-cleaving activity of hmeprin resembles that of gelatinases rather than collagenases. Hmeprin is inhibited by hydroxamic acid derivatives such as batimastat, galardin and Pro-Leu-Gly-hydroxamate, by TAPI-0 (tumour necrosis factor alpha protease inhibitor-0) and TAPI-2, and by thiol-based compounds such as captopril. Therapeutic targets for these inhibitors are MMPs (matrix metalloproteases), TACE (tumour necrosis factor alpha-converting enzyme) and angiotensin-converting enzyme respectively. The most effective inhibitor of hmeprin alpha in the present study was the naturally occurring hydroxamate actinonin ( K(i)=20 nM). The marked variance in the cleavage specificities of hmeprin alpha and beta is reflected by their interaction with the TACE inhibitor Ro 32-7315, whose affinity for the beta subunit (IC50=1.6 mM) is weaker by three orders of magnitude than that for the alpha subunit ( K(i)=1.6 microM). MMP inhibitors such as the pyrimidine-2,4,6-trione derivative Ro 28-2653 that are more specific for gelatinases do not bind to hmeprin, presumably due to the subtle differences in the mode of zinc binding and active-site structure between the astacins and the MMPs.

Animals↗
PubMed2004

Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

Animals↗
PubMed2004

TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

Animals↗
PubMed2003

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.

Adult↗
PubMed2003

Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells.

IL-12 p40-related cytokines such as IL-12 p35/p40 heterodimer and IL-23 (p19/p40) are potent regulators of adaptive immune responses. Little is known, however, about the transcriptional regulation of the p40 gene in vivo. In an attempt toward this goal, we have generated transgenic mice expressing firefly luciferase under the control of the IL-12 p40 promoter. High constitutive transgene expression was found in the small intestine only, whereas little reporter gene activity was observed in other tissues. Within the small bowel, constitutive promoter activity was restricted to the terminal ileum and associated with high expression of p40 mRNA as well as p40 and IL-23 p19/p40 proteins. The cells constitutively producing IL-12 p40 were identified as CD8alpha and CD11b double-negative CD11c+ lamina propria dendritic cells (LPDCs) that represent a major cell population in the lamina propria of the small intestine, but not in the colon. FISH directly demonstrated the uptake of bacteria by a subset of LPDCs in the terminal ileum that was associated with p40 expression. Furthermore, little or no p40 protein expression in LPDCs was found in the terminal ileum of germfree mice, indicating a key role of the intestinal flora for constitutive p40 expression. In addition, analysis of transgenic mice with a mutated NF-kappaB target site in the p40 promoter showed a critical role of NF-kappaB for constitutive transgene expression. Our data reveal important functional differences between the mucosal immune systems of the small and large bowel in healthy mice and suggest that the high bacterial load in the terminal ileum activates p40 gene transcription in LPDCs through NF-kappaB. These data suggest a predisposition of the terminal ileum to develop chronic inflammatory responses through IL-23 and thus may provide a molecular explanation for the preferential clinical manifestation of Crohn disease in this part of the gut.

Animals↗
PubMed2003

Differences in the activation mechanism between the alpha and beta subunits of human meprin.

Meprins are zinc-endopeptidases of the astacin family, which are expressed as membrane-bound or secreted forms in renal and intestinal brush-border membranes of mouse, rat and man. There are two types of meprin subunits, alpha and beta, which form disulfide-bonded homo- and heterodimers; further oligomerization is mediated by non-covalent interactions. Both subunits are translated as proenzymes that have to be activated by removal of an N-terminal propeptide. In the gut, the most probable activator is trypsin. In addition, plasmin has been shown to activate the human alpha subunit in colorectal cancer tissue. In the present study we have overexpressed the human meprin alpha subunit and a His-tagged soluble tail-switch-mutant of meprin beta in Baculovirus-infected insect cells. The recombinant homo-oligomeric proteins were purified by gel filtration and affinity chromatography with yields of up to 10 mg/l cell culture medium and analyzed with regard to their activation mechanism. While both alpha and beta homo-oligomers are activated by trypsin, only meprin alpha homo-oligomers are processed to their mature form by plasmin. These results indicate a different accessibility of the propeptide in meprin homo-oligomers and suggest an explanation for the appearance of meprin hetero-oligomers consisting of active alpha, but latent beta subunits.

Chromatography, Gel↗
PubMed2003

Acute portal hemodynamics and cytokine changesfollowing selective transarterial chemoembolization in patients with cirrhosis and hepatocellular carcinoma.

BACKGROUND: Altered portal hemodynamics and inflammation may occur following transcatheter arterial chemoembolization (TACE), but early biological and portal perfusion changes are not well characterized when this procedure is performed selectively. MATERIAL/METHODS: We studied variations in portal flow velocity (PFV) using Doppler ultrasonography, as well as serum TNFa, vCAM-1, and E-Selectin at 2 and 24 hours after supraselective TACE in 15 consecutive patients with cirrhosis and hepatocellular carcinoma. RESULTS: Variations in PFV occurred both in the embolized and non-embolized liver lobe. PFV increased significantly at 2 hours in the right and left portal vein. At 24 hours, right PFV remained elevated. Serum TNFa increased significantly at 2 hours, but VCAM-1 and E-Selectin levels remained unchanged. Changes in right and left PFV showed a positive correlation (r=0.9, p<0.001). No correlation could be observed between biological and Doppler changes in portal veins. CONCLUSIONS: In patients with cirrhosis and hepatocellular carcinoma, PFV increased in both liver lobes 2 hours after supraselective TACE, in association with high serum TNFa. Diffuse changes in PFV after TACE suggests that mechanisms involved in the regulation of portal and hepatic arterial hemodynamics are present in patients with cirrhosis. A major role for TNFa in acute portal flow velocity variations is unlikely in this situation.

Aged↗
PubMed2002

Intraindividual comparison of contrast-enhanced electron-beam computed tomography and navigator-echo-based magnetic resonance imaging for noninvasive coronary artery angiography.

The aim of this study was to compare contrast-enhanced electron-beam computed tomography (EBCT) and navigator-echo-based MRI of the coronary arteries in the same patient population. Both methods were assessed for visualization of the coronary arteries and their diagnostic accuracy in identifying significant coronary artery stenoses compared with conventional coronary angiography. Twenty patients with known coronary artery disease were examined with both contrast-enhanced EBCT and a respiratory-gated MRI sequence. A grading system was used to evaluate the image quality. Sensitivity and specificity for the detection of significant coronary artery stenoses was evaluated compared with conventional coronary angiography. With EBCT, 89% of the main coronary arteries could be completely visualised in the proximal and middle segments; with MRI, 83% were visualised. With EBCT the sensitivities for identifying significant (>/=50%) stenoses in proximal and middle vessel segments were 75% in the main stem, 88% in the left anterior descending coronary artery, 75% in the left circumflex coronary artery, and 90% in the right coronary artery. Respective sensitivities for MRI angiograms were 75, 82, 75 and 80%. With both modalities a sufficient image quality of the main coronary arteries can be obtained in most cases. The diagnostic capability for detecting significant stenoses is comparable for both methods.

Contrast Media↗
PubMed2002

Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA.

Recent studies have shown that IL-18, a pleiotropic cytokine that augments IFN-gamma production, is produced by intestinal epithelial cells and lamina propria cells from patients with Crohn's disease. In this study, we show that IL-18 is strongly expressed by intestinal epithelial cells in a murine model of Crohn's disease induced by transfer of CD62L+ CD4+ T cells into SCID mice. To specifically down-regulate IL-18 expression in this model, we constructed an E1/E3-deleted adenovirus expressing IL-18 antisense mRNA, denoted Ad-asIL-18, and demonstrated the capacity of such a vector to down-regulate IL-18 expression in colon-derived DLD-1 cells and RAW264.7 macrophages. Local administration of the Ad-asIL-18 vector to SCID mice with established colitis led to transduction of epithelial cells and caused a significant suppression of colitis activity, as assessed by a newly developed endoscopic analysis system for colitis. Furthermore, treatment with Ad-asIL-18 induced a significant suppression of histologic colitis activity and caused suppression of mucosal IFN-gamma production, whereas IFN-gamma production by spleen T cells was unaffected. Taken together, these data indicate an important role for IL-18 in the effector phase of a T cell-dependent murine model of colitis and suggest that strategies targeting IL-18 expression may be used for the treatment of patients with Crohn's disease.

Adenoviridae↗
PubMed2002

Multidetector computed tomography (MDCT) in coronary surgery: first experiences with a new tool for diagnosis of coronary artery disease.

BACKGROUND: Selective coronary angiography (SCA) is the standard invasive procedure for diagnosis in patients eligible for coronary artery bypass grafting (CABG). A recently developed, highly sensitive multidetector computed tomography (MDCT) scan holds promise to be of almost comparable quality and predictiveness. We examined a blinded series of preoperative patients who were admitted to hospital for conventional and minimally invasive CABG procedures. Patients underwent CT scans in addition to SCA; findings were compared regarding location and degree of coronary artery stenosis. METHODS: Twenty patients underwent electrocardiogram-gated helical CT scanning. Images with 250 ms effective exposure time were reconstructed with retrospective electrocardiogram gating. Location and degree of coronary stenoses were described and compared with findings of SCA. The study was limited to patients with a heart rate of less than 70 beats per minute and who had the ability to hold their breath for 20 to 30 seconds. RESULTS: Coronary arteries were clearly displayed by MDCT. Compared with SCA, sensitivity was 92%, specificity 84%, and negative predicted value 89% for significant stenosis (more than 50%). Early forms of atherosclerotic changes were even clearer on MDCT. In addition, the CT examination allowed differentiation of calcified and fatty or fibrous stenoses. CONCLUSIONS: Multidetector CT scanning is an effective noninvasive technique for the diagnosis of coronary artery disease. In selected patients, MDCT scanning might be able to replace SCA as a preoperative test for CABG procedures. The intrathoracic situs can be clearly exposed as it is important for the planning of minimally invasive CABG procedures.

Coronary Angiography↗
PubMed2002

Determination of coronary calcium with multi-slice spiral computed tomography: a comparative study with electron-beam CT.

Electron-beam Computed Tomography (EBCT) has been used for years to quantify coronary artery calcification as a marker of coronary atherosclerosis. The aim of this study was to determine the diagnostic accuracy of a new scanner, the Multi-slice Spiral CT (MSCT), for the assessment of coronary calcification and to compare this new technique to EBCT. The study population consisted of 99 male patients, aged 60 +/- 10 years with suspected or known coronary artery disease. With EBCT 40 axial slices, ECG-triggered (scan time = 100 ms, slice thickness = 3 mm), were acquired in one breath-hold (35 +/- 5 s). For MSCT simultaneous acquisition of four axial slices (scan time = 250 ms, slice thickness = 2.5 mm), allowed the entire heart (48 slices) to be covered in one breath-hold of 25 +/- 5 s. For quantification of coronary calcium the Volumetric Calcium Score (VCS) was calculated. There was an excellent correlation for the VCS (r = 0.994, p = 0.01, mean difference = 97 +/- 115) between both scanners. Comparison of low (1-100), moderate (101-400), high (401-1000) and very high score values (>1,000) showed no significant differences. The number of calcified lesions and densities were statistically not different. Mean variability of the two scans was 17%. The MSCT scanner is equivalent to EBCT for the determination and quantification of coronary calcium and can therefore be used for calcium screening. With application of the spiral mode technique further improvement in variability can be expected, thus allowing for follow-up studies to determine progression or regression of atherosclerosis with high accuracy.

Calcinosis↗
PubMed2002

Influence of anti-CD49f and anti-CD29 monoclonal antibodies on mitotic activity of epithelial cells (HaCaT) and gingival fibroblasts in vitro.

A major complication in the treatment of periodontitis marginalis is the reepithelization of periodontal defects inhibiting collagen fiber attachment and periodontal regeneration. In this study we investigated the possibility of a molecular blockade of epithelial mitosis in vitro. Monoclonal antibodies against the VLA-6 laminin receptor subunit alpha6 interrupted interactions between epithelial cells (HaCaT cells) and their extracellular matrix and thus resulted in reduction of proliferation rates by more than 50%. The same effect was observed with anti alpha1-antibodies. In contrast, collagen-producing and -secreting gingival fibroblasts, which play an important role in periodontal regeneration, remained unaffected by the applied anti alpha6 antibodies. Correspondingly, these cells were found to lack VLA-6 laminin receptors. Selective molecular inhibition of epithelial proliferation and apical migration by monoclonal anti alpha6 antibody application may provide an adjuvant periodontitis therapy resulting in an enhanced periodontal regeneration.

Antibodies, Monoclonal↗
PubMed2002

Computed tomography-fluoroscopy guided drainage of pericardial effusions: experience in 11 cases.

RATIONALE AND OBJECTIVES: The purpose of the study was to evaluate feasibility and safety of CT-fluoroscopy in the drainage of pericardial effusion in cases not accessible by sonography. METHODS: Eleven drainages were performed in Seldinger-technique under CT-fluoroscopy on eight patients suffering from pericardial effusion. The inclusion criterion was a sonographically proved pericardial effusion not drainable under sonographic surveillance. In seven procedures the catheter was positioned using a medial, in four procedures a lateral approach from the apex was chosen. RESULTS: All catheters could be placed successfully (11/11) in the pericardial effusion and allowed for draining of the effusion in 10 of 11 cases. One epicardial laceration necessitated a surgical approach. The elapsed total procedure time for the drainage was on average 18:23 +/- 8:58 minutes. CONCLUSIONS: Visual surveillance by CT-fluoroscopy is a feasible method in the drainage of pericardial effusions even in cases not accessible by ultrasound.

Adult↗
PubMed2002

Reproducibility and accuracy of coronary calcium measurements with multi-detector row versus electron-beam CT.

PURPOSE: To methodically evaluate the reproducibility and accuracy of coronary arterial calcification measurements by using spiral multi-detector row and electron-beam computed tomography (CT) with a beating heart phantom. MATERIALS AND METHODS: A phantom was built to mimic a beating heart with coronary arteries and calcified plaques. The simulated vessels moved in a pattern similar to that of a beating heart. The phantom operated at a variety of pulse rates (0-140 beats per minute). The phantom was repeatedly scanned in various positions by using various protocols with electron-beam and multi-detector row CT scanners to assess interexamination variability. Statistical analysis was performed to determine significant differences in interexamination variability for various acquisition protocols. RESULTS: Electrocardiographically (EKG) gated volume coverage with spiral multi-detector row CT (2.5-mm collimation) and overlapping image reconstruction (1-mm increment) was found to significantly improve the reliability of coronary arterial calcium quantification, especially for small plaques (P <.05). Mean interexamination variability was reduced from 35% +/- 6 (SD) (Agatston score, standard electron-beam CT) to 4% +/- 2 (P <.05) (volumetric score, spiral EKG-gated multi-detector row CT). CONCLUSION: By coupling retrospective gating with nearly isotropic volumetric imaging data, spiral multi-detector row CT provides better input data for quantification of coronary arterial calcium volume. Multi-detector row CT allows precise and repeated measurement of coronary arterial calcification, with low interexamination variability.

Calcinosis↗
PubMed2002

Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36.

The existence of an intracellular pool of fatty acid translocase (FAT/CD36), an 88-kDa membrane transporter for long-chain fatty acids (FAs), and the ability of insulin to induce translocation events prompted us to investigate the direct effects of insulin on cellular uptake of FA by the heart. Insulin (0.1 nmol/l and higher) increased FA uptake by isolated rat cardiac myocytes by 1.5-fold. This insulin-induced increase in FA uptake was completely blocked by phloretin, sulfo-N-succinimidylpalmitate (SSP), and wortmannin, indicating the involvement of FAT/CD36 and the dependence on phosphatidylinositol-3 (PI-3) kinase activation. Subcellular fractionation of insulin-stimulated cardiac myocytes demonstrated a 1.5-fold increase in sarcolemmal FAT/CD36 and a 62% decrease in intracellular FAT/CD36 with parallel changes in subcellular distribution of GLUT4. Induction of cellular contractions upon electrostimulation at 4 Hz enhanced cellular FA uptake 1.6-fold, independent of PI-3 kinase. The addition of insulin to 4 Hz-stimulated cells further stimulated FA uptake to 2.3-fold, indicating that there are at least two functionally independent intracellular FAT/CD36 pools, one recruited by insulin and the other mobilized by contractions. In conclusion, we have demonstrated a novel role of insulin in cardiac FA utilization. Malfunctioning of insulin-induced FAT/CD36 translocation may be involved in the development of type 2 diabetic cardiomyopathies.

Androstadienes↗