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.

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]. / 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

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.

Clinical characteristics of patients with obstructive coronary lesions in the absence of coronary calcification: an evaluation by coronary CT angiography.

BACKGROUND: Multidetector CT allows detection of coronary artery calcium and, after contrast injection, visualisation of the coronary artery lumen. It is commonly assumed that the absence of coronary calcification makes the presence of obstructive coronary lesions highly unlikely. This study evaluates the clinical characteristics of patients with at least one symptomatic, high-grade coronary artery stenosis in both computed tomography and invasive angiography but absence of any coronary calcification and compares the results with patients with stenoses in the setting of detectable coronary calcium PATIENTS AND METHODS: The study retrospectively identified 21 consecutive patients with symptoms in whom a high-grade coronary artery stenosis had been identified in 64-slice or dual-source CT coronary angiography (Siemens Sensation 64 or Siemens Definition, 120 kV, 50 to 85 ml of intravenous contrast at 5 ml/s) in the absence of coronary calcium and in whom that finding had been confirmed by invasive coronary angiography. Clinical presentation ("unstable": all forms of acute coronary syndrome versus "stable": stable chest pain or dyspnoea on exertion) and standard cardiovascular risk factors were assessed, and the results were compared with 42 consecutive patients with symptoms in whom both coronary calcium and coronary stenoses had been identified in computed tomography and invasive coronary angiography. RESULTS: The majority of patients with coronary stenoses in the absence of coronary calcium presented with "unstable" symptoms (non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina), significantly more frequently than patients with detectable calcification (71% vs 26%, p = 0.001). The age range of patients without calcium was 33 to 76 years, their mean age was younger (53 (SD 13) vs 63 (8) years, p<0.001), but none of the risk factors showed any significant difference compared with patients with calcification. CONCLUSION: The presence of significant coronary artery stenosis in the absence of coronary calcium is possible. It is more likely in the setting of unstable angina or NSTEMI than in stable chest pain and occurs more frequently in younger patients.

[Septal delineation using a 20 % diluted contrast chaser bolus in coronary CT angiography: a comparison of 64-slice and dual source CT]. / Abgrenzbarkeit des interventrikulären Septums mit einem 20 % Kontrastmittelspülbolus in der CT-Koronarangiografie: Ein Vergleich von 64-Schicht- und Dual-Source-CT.

PURPOSE: Due to the technical advance of multislice cardiac CT and the recently introduced dual source CT, the acquisition times for cardiac CT exams are < 10 sec. At the same time the assessment of left ventricular function is possible. However, in many patients a complete right ventricular outwash is noted, leading to insufficient septal delineation. Studies were able to demonstrate that contrast media (CM) mixed in the saline chaser bolus is sufficient for significantly better visualization of septal structures. The aim of this study was to investigate whether this dual flow concept works as well for 64-slice and dual source CT angiography using only 20 % CM in the saline chaser bolus. MATERIALS AND METHODS: 97 patients were included in this prospective study. 47 patients underwent 64-slice CT coronary angiography. 80 cc were administered at 5 cc/sec as the main bolus followed by a 50 cc saline chaser bolus containing 20 % contrast media. The other 50 patients were examined using dual source CT. They received a CM protocol adapted for the scan time with the identical saline/CM chaser bolus. The datasets were quantitatively examined in defined ROIs along the septum and in the right ventricle with respect to the density. The septal delineation was qualitatively analyzed and both groups were compared. In a final step the density was measured in the proximal and distal RCA as well as in the LAD and also compared. RESULTS: Using the protocol adapted for the scan time, significantly less CM was used. No significant difference was able to be found regarding the septal delineation or coronary enhancement. CONCLUSION: The study shows that the dual flow concept allows for robust septal delineation regardless of the CM injection protocol used as long as a 20 % saline chaser bolus is used. A CM protocol adapted for the scan time also leads to significant CM reduction at equal image quality.

[Initial experience with prospectively triggered, sequential CT coronary angiography on a 128-slice scanner]. / Erste Erfahrungen mit der sequenziellen, prospektiv getriggerten CT-Koronarangiografie an einem 128-Schicht-Computertomografen.

PURPOSE: Spiral CT angiography (CTA) of the coronaries using low-pitch scanning and ECG-gated image reconstruction is a robust method for detecting or excluding relevant coronary plaque. However, the resulting dose exposure is considerable. The aim of the present study was to evaluate image quality and artifacts as well as to record dose values for sequential coronary CTA using a 128-slice scanner with a temporal resolution of 150 ms. MATERIALS AND METHODS: 20 patients with a regular heart rate and without contraindications for oral/I.V. beta blockers, who were referred for CTA of the coronaries for exclusion or detection of relevant plaques, were examined by sequential CTA with the following parameters: 120 kV, 200 ref mAs, collimation 2 x 64 x 0.6, table feed of 34.5 mm at a detector width of 38.4 mm. A total acquisition time of 380 ms per table position allowed for mild shifting of the reconstruction window within the cardiac cycle of +/- 5 %. 50 ml of contrast agent were injected at 5 ml/s followed by a 50 ml split bolus (20 % contrast). The individual start delay was determined by a test bolus scan (10 ml contrast + 50 ml saline flush at 5 ml/s). The image quality for each segment, coronary artery, and patient was determined on a 4-point scale. Dose values were estimated based on the individual dose length product as provided by the scanner's patient protocol. Artifacts were evaluated to determine the cause (calcium vs. motion). RESULTS: All patients received beta blocker pretreatment. The mean heart rate was 62 +/- 5 beats/min. 5 % (13 / 286) of all segments in 5 / 20 patients were rated as non-diagnostic. The mean dose length product was 213 mGy x cm, and the mean effective dose was 3.6 mSv. Calcifications were the major cause of non-diagnostic images. However breathing or other motion artifacts occurred as well. CONCLUSION: In select patients with effective heart rate control and thorough instruction for breath hold compliance, sequential CTA of the coronaries using a 128-slice scanner with a temporal resolution of 150 ms is technically feasible. The resulting effective dose values are clearly below those of spiral coronary CT scans.

Assessment of regional left ventricular function by dual source computed tomography: interobserver variability and validation to laevocardiography.

OBJECTIVE: Assessment of left ventricular function is possible in contrast-enhanced cardiac CT data sets. However, rapid ventricular motion especially in systole can lead to artifacts. Dual Source Computed Tomography (DSCT) has high temporal resolution which effectively limits motion artifact. We therefore assessed the accuracy of DSCT to detect regional left ventricular wall motion abnormalities in comparison to invasive cine angiocardiography. METHODS: We analyzed DSCT data sets of 50 patients (39 male, 11 female, mean age: 61+/-10 years) which were acquired after intravenous injection of 55-70 mL contrast agent (rotation time: 330 ms, collimation: 2 mm x 64 mm x 0.6 mm, 120 kV, 380 mAs, ECG-correlated tube current modulation). 10 data sets consisting of transaxial slices with a slice thickness of 1.5 mm, an increment of 1.0 mm and a matrix of 256 x 256 pixels were reconstructed at 10 time instants during the cardiac cycle (0-90% in 10% increments). The data sets were analyzed visually by two independent readers, using standard left ventricular planes, concerning regional wall motion abnormalities. DSCT was verified in a blinded fashion against cine ventriculography performed during cardiac catheterization (RAO and LAO projection), using a 7-segment model. Analysis was performed on a per-patient (presence of at least one hypo-, a- or dyskinetic segment) and on a per-segment basis. RESULTS: Concerning the presence of a wall motion abnormality, the two observers agreed in 340/350 segments (97%) and 48/50 patients (96%). In invasive cine angiocardiography, 22 of 50 patients displayed at least one segment with abnormal contraction. To detect these patients, DSCT showed a sensitivity of 95% (21/22), specificity of 96% (27/28), positive predictive value of 95% and negative predictive value of 96%. Out of a total of 350 left ventricular segments, 66 segments had abnormal contraction in cine angiocardiography (34 hypokinetic, 26 akinetic, 6 dyskinetic). For detection of these segments, DSCT had a sensitivity of 88% (58/66), specificity of 98% (278/284), positive predictive value of 91% (58/64) and negative predictive value of 97% (278/286). CONCLUSION: DSCT allows the detection of regional wall motion abnormalities with high interobserver agreement as well as high sensitivity and specificity. Whereas sensitivity and positive predictive value were higher in a per-patient- in comparison to a per-segment-based analysis, specificity, negative predictive value and interobserver agreement did not differ considerably between both analyzing methods.

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.

[Chance finding of a bilateral central pulmonary embolism while using cardiac computed tomography for the clarification of a coronary anomaly]. / Zufallsbefund beidseitiger zentraler Lungenembolien bei kardialer Computertomographie zur Klärung einer Koronaranomalie.

HISTORY: A 42 year-old man reported transient breathlessness and chest pain on the first day after a four-hour flight. During the following five months the symptoms recurred four times. After another episode he went to an outpatient department for further assessment. INVESTIGATIONS: Blood tests demonstrated slightly elevated LDH (343 U/l) and also a minor increase of the D-dimers (710 microg/l). Hypercholesterolemia was also found (LDL-cholesterol 180 mg/dl). The rest of the blood tests, including the cardiac enzymes, were within normal limits. The electrocardiogram (ECG) showed sinus rhythm, heart rate 85 bpm and pre-terminal T-negativity in the precordial leads V1 to V3. Resting echocardiography and chest X-ray showed no significant abnormalities. The exercise ECG demonstrated no further ECG changes. However, because of the symptoms and a cardiovascular risk profile (family history, hypercholesterolemia and smoking) a coronary angiography was performed, which excluded coronary artery disease but revealed a so-called "right-sided single coronary artery", the left and right coronary arteries originating with a common stem from the right sinus of valsalva. To define the exact course of the left main coronary artery (whether in front of the pulmonary artery, between the two great arteries, retroaortic or septal) a contrast-enhanced cardiac computed tomography (CT) was performed, which demonstrated an anomalous position of the left main coronary artery in front of the pulmonary artery. Bilateral pulmonary embolism was an additional and unexpected finding. TREATMENT AND COURSE: Oral anticoagulation was initiated after a coagulopathy had been excluded. The ultrasonography of the leg did not demonstrate any thrombosis. There was no evidence of malignant disease. CONCLUSION: Mild symptoms and absence of right heart congestion do not exclude pulmonary embolism. Depending on the symptoms and history, pulmonary thrombembolism has to be considered, especially if cardiac or extra-cardiac causes have been eliminated. The diagnostic method of choice for the detection or exclusion of pulmonary embolism is contrast-enhanced multi-slice spiral CT.