[Optimal stroke prevention in the geriatric patient with atrial fibrillation: position paper of an interdisciplinary expert panel]. / Optimale Schlaganfallprävention bei geriatrischen Patienten mit Vorhofflimmern. Konsensbericht eines interdiszipIinären Expertengremiums.

BACKGROUND: The optimal approach to stroke prevention in geriatric patients with atrial fibrillation (AF) has not been adequately clarified. Despite their high risk of stroke and clear indication for anticoagulation according to established risk scores, in practice geriatric AF patients often are withheld treatment because of comorbidities and comedications, concerns about low treatment adherence or fear of bleeding events, in particular due to falls. METHOD: The present position paper summarises the outcomes of an expert panel discussion held by hospital-based and office-based physicians with ample experience in the treatment of geriatric patients. RESULTS AND CONCLUSIONS: The panel agreed that geriatric patients should receive oral anticoagulation as a rule, unless a comprehensive neurological and geriatric assessment (including clinical examination, gait tests and validated instruments such as Modified Rankin Scale, Mini-mental state examination or Timed Test of Money Counting) provides sound reasons for refraining from treatment AII patients with a history of falls should be thoroughly evaluated for further evaluation of the causes. Patients with CHADS2 score ≥ 2 should receive anticoagulation even if at high risk for falls. The novel oral anticoagulants (NOAC) facilitate management in the geriatric population with AF (no INR monitoring needed, easier bridging during interventions) and have an improved benefit-risk ratio compared to vitamin K antagonists. Drugs with predominantly non-renal elimination are safer in geriatric

Differentiation of total occlusion and high-grade stenosis in coronary CT angiography.

In coronary CT angiography (CTA), both high-grade stenoses and total occlusions of a coronary artery may appear as a complete interruption of the contrast-enhanced lumen. Parameters to differentiate between occlusions and stenoses have not been systematically assessed. We evaluated 40 consecutive patients with a lesion demonstrating complete interruption of the contrast-enhanced lumen in coronary CTA and in whom invasive coronary angiography was available. Length of the vessel segment without luminal contrast enhancement; luminal enhancement proximal, in and distal to the lesion; degree of coronary remodelling; and the degree of lesion calcification were assessed by a blinded observer unaware of the invasive angiogram. Mean length of complete occlusions (n = 20; range 4-54 mm; mean 16.6 +/- 3.5 mm) was significantly longer than for high-grade stenoses (n = 20; 2-8 mm; mean 4.6 +/- 1.7 mm, p < 0.001). A lesion length > or = 9 mm was 100% specific and 70% sensitive for an occlusion. No significant differences were found for vessel enhancement in or distal to the lesion, remodelling index or degree of calcification. Lesion length is the only parameter that may differentiate complete occlusions and high-grade stenoses in coronary CTA. For lesions > or = 9 mm, an occlusion is very likely.

Interobserver variability of 64-slice computed tomography for the quantification of non-calcified coronary atherosclerotic plaque.

PURPOSE: Multidetector CT (MDCT) is a reliable tool to assess and quantify calcified plaque in coronary arteries. Only very limited information is available concerning the accuracy of MDCT for evaluating non-calcified plaque. We determined the interobserver variability for measuring non-calcified plaque volumes in the three main coronary arteries using 64-slice computed tomography. MATERIALS AND METHODS: We retrospectively evaluated data sets of 41 patients who received a 64-slice CT scan (Sensation 64, Siemens Forchheim, Germany, 330 msec rotation, 0.6 mm collimation, 60 ml contrast agent i. v. at 5 ml/sec) due to suspected stable coronary artery disease. The patients showed presence of non-calcified plaque in the proximal part of at least one main coronary artery. The image quality was defined on the basis of a 4-point rating scale. Two independent and blinded investigators measured the plaque volume of the non-calcified plaque by manually tracing plaque areas in contiguous cross-sectional reconstructions rendered along the vessel centerline using a slice thickness of 1 mm and an increment of 0.5 mm. The interobserver variability was evaluated and the influence of plaque volume and image quality on interobserver variability was determined. RESULTS: The mean volume of non-calcified plaque was 157 +/- 85 mm (3), 76 +/- 43 mm (3) and 133 +/- 80 mm (3) for the LAD, LCX and RCA, respectively (LAD vs. LCX: p < 0.01; LAD vs. RCA: p = 0.33; LCX vs. RCA: p < 0.01). There was a mean absolute difference in plaque volume between the two observers of 23 +/- 15 mm (3), of 20 +/- 9 mm (3) and of 38 +/- 21 mm (3), which corresponds to a mean interobserver variability of 17 +/- 10 %, 29 +/- 13 % and 32 +/- 13 % for the LAD, LCX and RCA, respectively (LAD vs. LCX: p < 0.01; LAD vs. RCA: p < 0.01; LCX vs. RCA: p = 0.87). A significant inverse correlation between interobserver variability and the extent of the plaque volume (r = - 0.48; p = 0.01) was found. Interobserver variability was dependent on image quality: The highest image quality was observed in the LAD (2.4 +/- 0.5), while the image quality in the LCX (2.1 +/- 0.7) and the RCA (2.0 +/- 0.6) was lower. CONCLUSION: Interobserver variability for the quantification of non-calcified plaque volumes in 64-slice MDCT is substantial. Interobserver variability in the LAD was significantly lower than in the LCX and the RCA. This might be due to a larger mean plaque volume and better image quality in the LAD than in other coronary arteries.

Conserved stem-loop structures in the HIV-1 RNA region containing the A3 3' splice site and its cis-regulatory element: possible involvement in RNA splicing.

The HIV-1 transcript is alternatively spliced to over 30 different mRNAs. Whether RNA secondary structure can influence HIV-1 RNA alternative splicing has not previously been examined. Here we have determined the secondary structure of the HIV-1/BRU RNA segment, containing the alternative A3, A4a, A4b, A4c and A5 3' splice sites. Site A3, required for tat mRNA production, is contained in the terminal loop of a stem-loop structure (SLS2), which is highly conserved in HIV-1 and related SIVcpz strains. The exon splicing silencer (ESS2) acting on site A3 is located in a long irregular stem-loop structure (SLS3). Two SLS3 domains were protected by nuclear components under splicing condition assays. One contains the A4c branch points and a putative SR protein binding site. The other one is adjacent to ESS2. Unexpectedly, only the 3' A residue of ESS2 was protected. The suboptimal A3 polypyrimidine tract (PPT) is base paired. Using site-directed mutagenesis and transfection of a mini-HIV-1 cDNA into HeLa cells, we found that, in a wild-type PPT context, a mutation of the A3 downstream sequence that reinforced SLS2 stability decreased site A3 utilization. This was not the case with an optimized PPT. Hence, sequence and secondary structure of the PPT may cooperate in limiting site A3 utilization.

Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors.

BACKGROUND: Recent studies demonstrated an influence of atherosclerotic risk factors on the progression of aortic valve stenosis. The extent of aortic valve calcification (AVC) was also found to be a strong predictor of stenosis progression. We investigated the influence of the LDL cholesterol level (LDL), other standard cardiovascular risk factors, and the extent of coronary calcification (CC) on the progression of AVC quantified by electron beam tomography (EBT). METHODS AND RESULTS: In 104 patients (64.7+/-8 years, 89 male) with an EBT scan positive for AVC, CC and AVC were quantified using a volumetric score. EBT was repeated at a mean interval of 15 months (10 to 36 months), and the progression of AVC and CC was determined. Patients were divided into 2 groups according to LDL: group 1, LDL3.36 mmol/L (130 mg/dL), 47 patients. Mean values for CC were 546+/-932 mm(3) in scan 1 and 665+/-1085 mm(3) in scan 2 for AVC 324+/-796 mm(3) and 404+/-1076 mm(3), respectively. The mean progression of CC was 27+/-37% (group 1, 16+/-22%; group 2, 39+/-46%, P

Detection of coronary artery stenoses by contrast-enhanced, retrospectively electrocardiographically-gated, multislice spiral computed tomography.

BACKGROUND: Multislice spiral computed tomography (MSCT) with retrospectively ECG-gated image reconstruction permits coronary artery visualization. We investigated the method's ability to identify high-grade coronary artery stenoses and occlusions. METHODS AND RESULTS: A total of 64 consecutive patients were studied by MSCT (4x1 mm cross-sections, 500-ms rotation, table feed 1.5 mm/rotation, intravenous contrast agent, retrospectively ECG-gated image reconstruction). All coronary arteries and side branches with a luminal diameter >/=2.0 mm were assessed concerning evaluability and the presence of high-grade stenoses (>70% diameter stenosis) or occlusions. Results were compared with quantitative coronary angiography. Of 256 coronary arteries (left main, left anterior descending, left circumflex and right coronary artery, including their respective side branches), 174 could be evaluated (68%). In 19 patients (30%), all arteries were evaluable. Artifacts caused by coronary motion were the most frequent reason for unevaluable arteries. Overall, 32 of 58 high-grade stenoses and occlusions were detected by MSCT (58%). In evaluable arteries, 32 of 35 lesions were detected, and the absence of stenosis was correctly identified in 117 of 139 arteries (sensitivity, 91%; specificity, 84%). If analysis was extended to all stenoses with >50% diameter reduction, sensitivity was 85% (40 of 47) and specificity was 76% (96 of 127). CONCLUSIONS: MSCT with retrospective ECG gating permits the detection of coronary artery stenoses with high accuracy if image quality is sufficient, but its clinical use may presently be limited due to degraded image quality in a substantial number of cases, mainly due to rapid coronary motion.

Noninvasive coronary angiography by retrospectively ECG-gated multislice spiral CT.

BACKGROUND: We investigated the applicability and image quality of contrast-enhanced coronary artery visualization by multislice spiral CT using retrospective ECG gating. METHODS AND RESULTS: Twenty-five patients in sinus rhythm (significant coronary artery stenoses ruled out by invasive angiography) were studied with a multislice spiral CT (Siemens SOMATOM Volume Zoom). In inspiration (mean breath-hold, 37 seconds), a volume data set of the heart was acquired (intravenous contrast agent; 4 x 1-mm slice thickness; 500-ms rotation; table feed, 1.5 mm/360 degrees ). Simultaneous recording of the ECG permitted retrospective reconstruction of contiguous cross sections in intervals of 1 mm at any desired interval of the cardiac cycle. The mean duration of the image reconstruction window was 185 ms. Next to 3-dimensional reconstructions of the heart and coronary arteries, multiplanar reconstructions were rendered to determine the visualized length of the coronary arteries, the contrast-to-noise ratio, and the correlation of coronary artery diameters to quantitative coronary angiography. CONCLUSIONS: The coronary arteries could be visualized over long segments (left main, 9+/-4 mm; left anterior descending, 112+/-34 mm; left circumflex, 80+/-29 mm; right coronary artery, 116+/-33 mm). On average, 78+/-16% of these distances were visualized free of motion artifacts. The mean contrast-to-noise ratio was 9.3+/-3.3. Coronary artery diameters in multislice spiral CT showed close correlation to quantitative coronary angiography (CT, 3.3+/-1.0 mm; angiography, 3. 2+/-0.9 mm; mean difference, 0.38 mm; r=0.86). Contrast-enhanced multislice spiral CT permits visualization of the coronary artery lumen. Further studies are necessary to determine whether image quality is sufficient to reliably detect coronary artery stenoses.

Noninvasive detection of coronary artery stenosis using contrast-enhanced three-dimensional breath-hold magnetic resonance coronary angiography.

OBJECTIVES: The purpose of this study was to evaluate a contrast-enhanced three-dimensional (3D) breath-hold magnetic resonance (MR) technique for detection of coronary artery stenoses. BACKGROUND: The accuracy of previously published MR coronary angiography protocols varies widely. Recently, coronary artery imaging using T1-shortening contrast agent has become possible, but so far there are no data concerning its clinical application. METHODS: Magnetic resonance coronary angiography was performed in 50 patients with suspected coronary artery disease. Magnetic resonance data acquisition using an ultrafast 3D gradient-echo sequence lasted over 32 heartbeats within one single breath-hold. Twenty milliliters of gadopentetate dimeglumine was injected at a flow rate of 1 ml/s for two successive studies covering the main coronary arteries in single-oblique planes. Stenosis assessment by MR was compared with significant (diameter stenosis > 50%) stenoses on X-ray angiography. Evaluation was limited to the proximal and mid-coronary artery segments. RESULTS: Two hundred sixty-eight of 350 artery segments (76.6%) could be evaluated. Left circumflex coronary artery was only evaluable in 50% of cases by MR. In the evaluable segments, 48 of 56 stenoses and 193 of 212 nonstenotic segments were correctly classified by MR. On a patient basis, MR correctly identified 34 of 36 patients with and 8 of 14 patients without significant coronary stenoses as demonstrated by X-ray angiography (sensitivity 94.4%, specificity 57.1%). CONCLUSIONS: Oblique projection contrast-enhanced MR coronary angiograms obtained within one single breath-hold permit identification of patients with coronary stenoses in the proximal and mid segments of the major coronary arteries with satisfactory accuracy.

Understanding carbon catabolite repression in Escherichia coli using quantitative models.

Carbon catabolite repression (CCR) controls the order in which different carbon sources are metabolized. Although this system is one of the paradigms of the regulation of gene expression in bacteria, the underlying mechanisms remain controversial. CCR involves the coordination of different subsystems of the cell that are responsible for the uptake of carbon sources, their breakdown for the production of energy and precursors, and the conversion of the latter to biomass. The complexity of this integrated system, with regulatory mechanisms cutting across metabolism, gene expression, and signaling, and that are subject to global physical and physiological constraints, has motivated important modeling efforts over the past four decades, especially in the enterobacterium Escherichia coli. Different hypotheses concerning the dynamic functioning of the system have been explored by a variety of modeling approaches. We review these studies and summarize their contributions to the quantitative understanding of CCR, focusing on diauxic growth in E. coli. Moreover, we propose a highly simplified representation of diauxic growth that makes it possible to bring out the salient features of the models proposed in the literature and confront and compare the explanations they provide.

Optimal Stroke Prevention in the Geriatric Patient with Atrial Fibrillation: Position Paper of an Interdisciplinary Expert Panel.

The present position paper summarises the outcomes of an expert panel discussion held by hospital-based and office-based physicians with ample experience in the treatment of geriatric patients. The optimal approach to stroke prevention in geriatric patients with atrial fibrillation (AF) has not been adequately clarified. Despite their high risk of stroke and clear indication for anticoagulation according to established risk scores, in practice geriatric AF patients often are withheld treatment because of comorbidities and comedications, concerns about low treatment adherence or fear of bleeding events, in particular due to falls. The panel agreed that geriatric patients should receive oral anticoagulation as a rule, unless a comprehensive neurological and geriatric assessment (including clinical examination, gait tests and validated instruments such as Modified Rankin Scale, Mini-mental state examination or Timed Test of Money Counting) provides sound reasons for refraining from treatment. All patients with a history of falls should be thoroughly evaluated for further evaluation of the causes. Patients with CHADS2 score ≥ 2 should receive anticoagulation even if at high risk for falls. The novel oral anticoagulants (NOAC) facilitate management in the geriatric population with AF (no INR monitoring needed, easier bridging during interventions) and have, based on available data, an improved benefit-risk ratio compared to vitamin K antagonists. Drugs with predominantly non-renal elimination are safer in geriatric patients and should be preferred.

Noninvasive, three-dimensional visualization of coronary artery bypass grafts by electron beam tomography.

Electron beam tomography (EBT, ultrafast computed tomography [CT], cine CT) combines unique temporal and high spatial resolution and is especially well suited for cardiac imaging. We established and evaluated a protocol for the noninvasive visualization and assessment of aortocoronary artery bypass grafts. Twenty-five patients with 56 bypass grafts were studied by EBT. Forty contiguous cross-sectional images were acquired triggered to the electrocardiogram during breathhold and intravenous injection of contrast agent. Three-dimensional reconstructions of the heart and bypass grafts were performed and compared with selective angiography of the bypass grafts. In 1 patient with 2 bypass grafts, a technically inadequate EBT examination was obtained. In the remaining patients (54 grafts), all 13 bypass occlusions were diagnosed with a sensitivity and specificity of 100%. Evaluation for hemodynamically relevant stenosis was possible in 84% of cases (36 of 43 patent grafts) and yielded a sensitivity of 100% (5 of 5 high-grade stenoses correctly detected) and specificity of 97% (1 false-positive diagnosis of high-grade graft stenosis). The main reasons for impaired ability to evaluate the scans were breathing artifacts and misplacement of the imaging volume, causing parts of the bypass grafts to be cut off. EBT permits noninvasive determination of bypass graft occlusion and relevant stenosis with high accuracy.

Visualization of coronary artery anomalies and their anatomic course by contrast-enhanced electron beam tomography and three-dimensional reconstruction.

Anomalous coronary arteries are rare conditions. However, they may cause myocardial ischemia and sudden death and their reliable identification is crucial for any imaging method that attempts coronary artery visualization. We studied the ability of contrast-enhanced electron beam tomography (EBT) to identify anomalous coronary arteries and their course. Thirty patients with previously identified coronary anomalies and 30 subjects with normal coronary anatomy were studied. By EBT, 40 to 50 axial images of the heart (3-mm slice thickness, 1 mm overlap, electrocardiographic trigger) were acquired in a single breathhold during continuous injection of contrast agent (160 ml, 4 ml/s). Based on the original images and 3-dimensional reconstructions, the EBT data were analyzed by 2 blinded observers as to the presence of coronary anomalies and their course. Results were compared with invasive angiography. EBT correctly identified all normal controls and all patients with coronary anomalies. The anatomic course of the coronary anomalies was correctly classified in 29 of 30 patients (97%), including right-sided origin of the left main coronary artery (n = 4) or of the left circumflex coronary artery (n = 15), left-sided origin of the right coronary artery (n = 9), and 1 coronary fistula from the left circumflex coronary artery to the right atrium. Only the distal anastomosis of a second fistula from the left circumflex coronary artery to a bronchial artery was not correctly identified. This study demonstrates that contrast-enhanced EBT is a reliable noninvasive technique to identify anomalous coronary arteries and their course.

Noninvasive coronary angiography by magnetic resonance imaging, electron-beam computed tomography, and multislice computed tomography.

In recent years, several techniques for noninvasive imaging of the coronary artery lumen (noninvasive coronary angiography) have been developed. These techniques include magnetic resonance imaging, electron-beam computed tomography, and, most recently, multislice computed tomography. Each of these techniques has specific advantages and disadvantages. Currently, EBCT seems to permit the most robust coronary artery imaging. In the future, imaging modalities will have to be further improved and validated in order to define specific areas for potential clinical applications.

Variability of repeated coronary artery calcium measurements by electron beam tomography.

In 120 patients, the mean interscan variability of coronary calcium quantification by electron beam tomography was 19.9% (median 7.8%) for the traditional calcium score, and 16.2% (median 5.7%) for volumetric scoring. Although this difference was not significant, there was a significant influence of the total amount of calcium, number of acquired images, and image noise on interscan reproducibility.

Visualization of the coronary arteries in three-dimensional reconstructions using respiratory gated magnetic resonance imaging.

OBJECTIVE: To assess the applicability of respiratory-gated magnetic resonance coronary angiography, combined with three-dimensional image reconstruction, for visualizing the coronary arteries. METHODS: Twenty subjects (three healthy volunteers and 17 patients without stenoses detected by coronary angiography) were investigated. Magnetic resonance imaging was performed in a 1.5 T scanner using ECG-triggered gradient-echo sequences to acquire a volume data set consisting of 24-48 contiguous axial cross-sections of the heart (2 mm slice thickness, 1.17 mm x 1.17 mm in-plane resolution). Navigator-echo-based retrospective respiratory gating was used to minimize respiratory motion artifacts. Three-dimensional reconstructions of the heart were rendered using surface-display techniques. The length of the visualized coronary arteries was measured in curved multiplanar reconstructions. RESULTS: In the three-dimensional reconstructions, the left main artery (LMA) and left anterior descending artery (LADA) were visualized in 17 cases, the left circumflex artery (LCXA) in 15, and the right coronary artery (RCA) in 16 cases. Vessel continuity was uninterrupted in all 17 cases for the LMA, in 14 for the LADA, eight for the LCXA, and 13 for the RCA. The mean lengths of the visualized vessels were 14 +/- 7 mm for the LMA, 65 +/- 13 mm for the LADA, 45 +/- 16 mm for the LCXA, and 37 +/- 26 mm for the RCA. Reasons for impaired visibility of the LCXA and RCA were poor image quality due to there being a low contrast:noise ratio, motion artifacts, and incomplete coverage by the imaging volume. CONCLUSIONS: Navigator-echo-based magnetic resonance imaging is a promising technique for investigating the coronary arteries. Acquisition of a volume data set permits three-dimensional displays of the coronary vessels.

Non-interventional cardiac diagnostics: computed tomography, magnetic resonance and real-time three-dimensional echocardiography. Techniques and clinical applications.

New cardiovascular imaging modalities, including computed tomography (CT), magnetic resonance (MR) imaging and real-time three-dimensional echocardiography, have great potential for providing important and additional information concerning cardiac function and pathology. With significant and extremely fast technical improvements, non-invasive cardiac imaging has become a focal point in the diagnosis of cardiac disease. Thereby CT has been shown to allow the visualization of coronary arteries concerning calcifications, significant stenoses and coronary plaques, whereas MR imaging demonstrated its ability to evaluate cardiac morphology and function as well as perfusion imaging and viability assessment. As CT and MR, real-time three-dimensional echocardiography has increasingly progressed in the last years offering the potential for routine clinical application, e.g. in the evaluation of valve disease, the assessment of left ventricular thrombi or the guidance of intracardiac catheter placement. This article will provide a brief overview of each technique, possible clinical applications and their perspectives. Because both, CT and MR, have been successfully applied to visualize the coronary arteries, this article focuses on the abilities and limitations of CT and MR coronary artery imaging.

[Influence of heart rate on image quality and detection of coronary stenoses with multislice spiral CT]. / Einfluss der Herzfrequenz auf die Bildqualität und den Nachweis von Koronarstenosen mittels 4-Zeilen-Spiral CT.

Multi-slice spiral CT (MSCT) permits the detection of coronary stenoses. We investigated the influence of the patient's heart rate (HR) during the scan on stenosis detection and the presence of motion artifacts. In 100 patients MSCT was performed and retrospectively ECG-gated cross-sectional images were reconstructed. 115 of 400 coronary arteries (29%) were unevaluable due to motion artifacts (84/115) or other reasons (31/115). In evaluable arteries, sensitivity was 91% (51/56 high grade stenoses detected), specificity was 89%. With increasing HR, the number of unevaluable arteries increased and overall sensitivity for stenosis detection decreased from 62% (HR < or = 70 bpm) to 33% (HR > 70 bpm). MSCT permits detection of coronary stenoses, but evaluability and accuracy decrease with increasing HR.

Qualitative modelling and formal verification of the FLR1 gene mancozeb response in Saccharomyces cerevisiae.

BACKGROUND: Qualitative models allow understanding the relation between the structure and the dynamics of gene regulatory networks. The dynamical properties of these models can be automatically analysed by means of formal verification methods, like model checking. This facilitates the model-validation process and the test of new hypotheses to reconcile model predictions with the experimental data. RESULTS: The authors report in this study the qualitative modelling and simulation of the transcriptional regulatory network controlling the response of the model eukaryote Saccharomyces cerevisiae to the agricultural fungicide mancozeb. The model allowed the analysis of the regulation level and activity of the components of the gene mancozeb-induced network controlling the transcriptional activation of the FLR1 gene, which is proposed to confer multidrug resistance through its putative role as a drug eflux pump. Formal verification analysis of the network allowed us to confront model predictions with the experimental data and to assess the model robustness to parameter ordering and gene deletion. CONCLUSIONS: This analysis enabled us to better understand the mechanisms regulating the FLR1 gene mancozeb response and confirmed the need of a new transcription factor for the full transcriptional activation of YAP1. The result is a computable model of the FLR1 gene response to mancozeb, permitting a quick and cost-effective test of hypotheses prior to experimental validation.