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International audience; Enceladus is the first planetary object for which direct sampling of a subsurface water reservoir, likely habitable, has been performed. Over a decade of flybys and seven flythroughs of its watery plume, the Cassini spacecraft determined that Enceladus possesses all the ingredients for life. The existence of active eruptions blasting fresh water into space, makes Enceladus the easiest target in the search for life elsewhere in the Solar System. Flying again through the plume with more advanced instruments, landing at the surface near active sources and collecting a sample for return to Earth are the natural next steps for assessing whether life emerges in this active world. Characterizing this habitable world also requires detailed mapping and monitoring of its tidally-induced activity, from the orbit as well as from the surface using complementary platforms. Such ambitious goals may be achieved in the future in the framework of ESA large or medium-class missions in partnership with other international agencies, in the same spirit of the successful Cassini-Huygens mission. For all these reasons, exploring habitable ocean worlds, with Enceladus as a primary target, should be a priority topic of the ESA Voyage 2050 programme.

BackgroundMultiple breath washout (MBW) using sulfur hexafluoride (SF6) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF6-MBW reference values in pulmonary healthy adults.MethodsWe evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20–88 years). Lung clearance index (LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from triplicate SF6-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI2.5) and 5% (LCI5) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile.ResultsAge was the only meaningful parameter influencing SF6-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in Sacin and 10% (CI 2% to 22%) in Scond. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in Sacin and 3% (CI 0% to 13%) in Scond.ConclusionSF6-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF6-MBW outcome parameters over the whole age range.Trial registration numberNCT04099225.

Background: SAD is common in patients with COPD. Occurring early in the course of the disease, it is frequently missed by currently used diagnostic tests. Multiple breath washout (MBW) testing detects ventilation heterogeneity (VH) while oscillometry (OS) assesses peripheral obstruction, both associated with SAD. We therefore set out to evaluate the presence and symptoms of SAD in patients with early COPD. Methods: We prospectively evaluated 26 patients (FEV1 77±19% pred., 88% GOLD I/II). In an 8-week cross-over design, the effect of dual bronchodilatation (tiotropium/olodaterol, T/O) on lung function and symptoms (CAT) was compared to monotherapy (formoterol). Lung function was assessed by spirometry, OS and SF6-MBW. Results: Patients with a high CAT dyspnoea item (≥3) had increased frequency dependence of resistance (D5-20, p Conclusions: SAD is present even in early COPD stages and associated with respiratory symptoms. These can be addressed with dual bronchodilatation exceeding the effect of monotherapy.

Ventilation heterogeneity is frequent in bronchial asthma and can be assessed using multiple breath wash-out testing (MBW). Most data is available in paediatric patients and using nitrogen as a tracer gas. We aimed to evaluate sulphur hexafluoride (SF6) MBW in adult asthmatics. Spirometry, whole-body plethysmography, impulse oscillometry and SF6-MBW were prospectively performed. MBW parameters reflecting global (lung clearance index, LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from three consecutive wash-outs. LCI was calculated for the traditional 2.5% and an earlier 5% stopping point that has the potential to reduce wash-out times. 91 asthmatics (66%) and 47 non-asthmatic controls (34%) were included in final analysis. LCI2.5 and LCI5 were higher in asthmatics (p acin and Scond were elevated (p 2.5 and 3.5% for LCI5 in asthmatics. Forty-one asthmatic patients had normal spirometry. ROC analysis revealed an AUC of 0.906 for the differentiation from non-asthmatic controls exceeding diagnostic performance of individual and conventional parameters (AUC = 0.819, p 6-MBW is feasible and reproducible in adult asthmatics. Ventilation heterogeneity is increased as compared to non-asthmatic controls persisting in asthmatic patients with normal spirometry. Diagnostic performance is not affected using an earlier LCI stopping point while reducing wash-out duration considerably.

Haufig bestehen bei Patienten mit chronisch obstruktiver Lungenerkrankung (COPD) begleitende Erkrankungen, die deren Morbiditat und Mortalitat erheblich beeinflussen. Die hochste Pravalenz haben kardiovaskulare Komorbiditaten. Dies lasst sich durch gemeinsame Risikofaktoren wie Tabakkonsum erklaren, wird aber zunehmend im Kontext von systemischen Inflammationsprozessen im Sinne eines „kardiopulmonalen Kontinuums“ gesehen. Von groser Bedeutung sind daruber hinaus lungenstrukturelle, pulmonal-vaskulare und genetische Faktoren. Aktuelle Leitlinien beziehen sich dennoch uberwiegend auf das Management der individuellen Erkrankung. Uberlappende Symptome, wie Dyspnoe oder thorakale Schmerzen, fuhren haufig zur Unterdiagnose begleitender kardialer oder pulmonaler Erkrankungen, die jeweils mit einer schlechteren Prognose vergesellschaftet ist. Zudem fuhrt die Angst vor Nebenwirkungen haufig zu einer unbegrundeten medikamentosen Unterversorgung mit typisch kardiovaskularen Wirkstoffen. Bei entsprechender Indikation bieten kardioselektive Betablocker ebenso wie langwirksame Bronchodilatatoren ein akzeptables Sicherheitsprofil. Theophyllin sowie hohe Dosen kurzwirksamer Bronchodilatatoren und oraler Steroide haben jedoch relevantes proarrhythmisches Potenzial. Obwohl die medikamentose Beeinflussung der systemischen Entzundung mit Steroiden oder Statinen attraktiv erscheint, wird das aktuelle Konzept den komplexen Wechselwirkungen nicht ganzlich gerecht. Kardiometabolische Erkrankungen gehen haufiger mit einer Affektion der luftleitenden Atemwege einher, wahrend Patienten mit vorherrschendem Emphysem haufiger an Sarkopenie („pulmonary wasting“) und Osteoporose leiden. Dies erfordert im Hinblick auf zukunftige diagnostische und therapeutische Strategien eine integrative Sichtweise und eine differenziertere Phanotypisierung der Krankheitsentitaten.

In postural stress, an increased preload volume leads to higher stroke volume (SV) according to the Frank-Starling law of the heart. The present study aimed to evaluate the hemodynamic response to postural stress using non-invasive inert gas rebreathing (IGR) in patients with normal as well as impaired left ventricular function. Hemodynamic measurements were performed in 91 patients undergoing cardiac magnetic resonance imaging (CMR). Mean cardiac output and SV determined by IGR were 4.4±1.3 l/min and 60±19 ml in the upright position, which increased significantly to 5.0±1.2 l/min and 75±23 ml in the supine position (P

Airways obstruction is frequent in patients with pulmonary hypertension (PH). Small airway disease (SAD) was identified as a major contributor to resistance and symptoms. However, it is easily missed using current diagnostic approaches. We aimed to evaluate more elaborate diagnostic tests such as impulse oscillometry (IOS) and SF6-multiple-breath-washout (MBW) for the assessment of SAD in PH. Twenty-five PH patients undergoing body-plethysmography, IOS and MBW testing were prospectively included and equally matched to pulmonary healthy and non-healthy controls. Lung clearance index (LCI) and acinar ventilation heterogeneity (Sacin) differed significantly between PH, healthy and non-healthy controls. Likewise, differences were found for all IOS parameters between PH and healthy, but not non-healthy controls. Transfer factor corrected for ventilated alveolar volume (TLCO/VA), frequency dependency of resistance (D5-20), resonance frequency (Fres) and Sacin allowed complete differentiation between PH and healthy controls (AUC (area under the curve) = 1.0). Likewise, PH patients were separated from non-healthy controls (AUC 0.762) by D5-20, LCI and conductive ventilation heterogeneity (Scond). Maximal expiratory flow (MEF) values were not associated with additional diagnostic values. MBW and IOS are feasible in PH patients both providing additional information. This can be used to discriminate PH from healthy and non-healthy controls. Therefore, further research targeting SAD in PH and evaluation of therapeutic implications is justified.

A novel algorithm of impedance cardiography referred to as electrical velocimetry (EV) has been introduced for non-invasive determination of cardiac output (CO). Previous validation studies yielded diverging results and no comparison with the non-invasive gold standard cardiac magnetic resonance imaging (CMR) has been performed. We therefore aimed to prospectively assess the accuracy and reproducibility of EV compared to CMR. 152 consecutive stable patients undergoing CMR were enrolled. EV measurements were taken twice before or after CMR in supine position and averaged over 20 s (AESCULON(®), Osypka Medical, Berlin, Germany). Bland-Altman analysis showed insufficient agreement of EV and CMR with a mean bias of 1.2 ± 1.4 l/min (bias 23 ± 26 %, percentage error 51 %). Reproducibility was high with 0.0 ± 0.3 l/min (bias 0 ± 8 %, percentage error 15 %). Outlier analysis revealed gender, height, CO and stroke volume (SV) by CMR as independent predictors for larger variation. Stratification of COCMR in quintiles demonstrated a good agreement for low values (4.4 l/min) with bias increasing significantly with quintile as high as 3.1 ± 1.1 l/min (p 0.001). Reproducibility was not affected (p = 0.71). Subgroup analysis in patients with arrhythmias (p = 0.19), changes in thoracic fluid content (p = 0.51) or left heart failure (p = 0.47) could not detect significant differences in accuracy. EV showed insufficient agreement with CMR and good reproducibility. Gender, height and increasing CO and SV were associated with increased bias while not affecting reproducibility. Therefore, absolute values should not be used interchangeably in clinical routine. EV yet may find its place for clinical application with further investigation on its trending ability pending.

Background: Multiple breath washout (MBW) showed promising results in the assessment of ventilation heterogeneity in pulmonary disease. However, the test is rather time consuming and according to current ERS/ATS recommendations three technically acceptable measurements should be reported. Available data for optimizing test methodology is mostly restricted to nitrogen based devices and infant lung disease. We therefore aimed to evaluate the number of required measurements in adults using sulfur hexafluoride MBW. Methods: LCI was derived from three consecutive MBW tests in pulmonary healthy controls (n=19) as well as patients suffering from COPD (n=33), bronchial asthma (n=32) and sarcoidosis (n=19). All patients were in clinically stable condition. Results: LCI significantly differed between controls (7.4±0.8), sarcoidosis (8.1±1.2), bronchial asthma (9.2±1.9) and COPD (10.8±2.2, p Conclusion: Reporting two valid LCI measurements seems to be sufficient in healthy controls as well as pulmonary disease. Absolute values are not altered while overall test time can be considerably reduced.

In patients with chronic obstructive pulmonary disease (COPD), cardiovascular comorbidities are highly prevalent and associated with considerable morbidity and mortality. This coincidence is increasingly seen in context of a “cardiopulmonary continuum” rather than being simply attributed to shared risk factors such as cigarette smoking. Overlapping symptoms such as dyspnea or chest pain lead to a worse prognosis due to missed concomitant diagnoses. Moreover, medication is often withheld as a result of unfounded concerns about side effects. Despite the frequent coincidence, current guidelines are still mostly restricted to the management of the individual disease. Future diagnostic and therapeutic strategies should therefore be guided by an integrative perspective as well as a refined phenotyping of disease entities.

Impedance cardiography measurement of cardiac output gained wide interest due to its ease of use and non-invasiveness. However, validation studies of different algorithms yielded diverging results. Bioreactance (BR) as a recent adaption differs fundamentally as the flow signal is derived from phase shifts. Our aim was to assess the accuracy and reproducibility of BR, as compared to the non-invasive gold standard-cardiac magnetic resonance imaging (CMR). We prospectively included 32 stable patients. BR was performed twice in the supine position and averaged over 30 seconds. Mean bias was 0.2 ± 1.8 l/minute (1 ± 28%, percentage error 55%) with limits of agreement ranging from −3.4 to 3.7 l/minute. Reproducibility was acceptable with a mean bias of 0.1 ± 0.9 l/minute (1 ± 14%, 27%). Low cardiac output was significantly overestimated (−1.1 ± 1.5 l/minute), while high cardiac output was underestimated (1.5 ± 1.7 l/minute), ( P=0.001), although reproducibility was unaffected. Bias and weight were moderately correlated in men (r = 0.50, P=0.02). No differences for accuracy were found in nine patients who had an arrhythmia (0.3 ± 1.4 versus 0.1 ± 2.0 l/minute, P=0.76), while clinically relevant differences were found in patients with mild aortic valve disease (1.9 ± 2.2 versus −0.3 ± 1.7 l/minute, P=0.02). Overall, BR showed insufficient agreement with CMR, overestimating low and underestimating high cardiac output states. Reproducibility was acceptable and not negatively affected by the circulatory condition. Consequently, absolute values acquired with BR should be interpreted with caution and must not be used interchangeably in clinical practice.

Local field potentials (LFP) reflect the integrated electrophysiological activity of a large group of neurons. To minimize influence of external activity on the analysis, conventionally bipolar recordings are used to eliminate volume-conducted signals. Here we introduce a novel method, called phase-coherence classification (PCC), to separate LFP in time-frequency domain into a volume-conducted, a local incoherent and local coherent signal. The PCC allows to compute the power spectral densities of each signal and to associate each class with possible locations of electro-physiological activity. In order to test the resolution properties and accuracy of the method we generate composite and non-stationary synthetic time series with similar statistical characteristics as measured LFP. The PCC identifies volume-conducted signals with a phase threshold that is determined from probability density functions of non-phase-shifted synthetic time series. We estimate optimal PCC parameters for the analysis of beta band oscillations in LFP and apply the PCC to a test data set obtained from within the subthalamic nucleus of eight patients with Parkinson’s disease (PD). We show that PCC can identify activity of multiple local clusters during a tremor episode and quantify the relative power of local and volume-conducted signals. We further analyze the electrophysiological response to an apomorphine injection during rest and show that incoherent activity in the low beta band shows a significant medication-induced decrease. We further find significant movement-induced changes on medication of the local coherent signal, which increased during an isometric hold task and decreased during phasic wrist movement. This indicates a different role of incoherent and coherent signals possibly related to physiologically different networks. This new PCC method can potentially also be applied to EEG and MEG data in order to minimize the influence of spatial leakage on power spectra and coherence estimates.

Background: Assessment of ILD includes measurement of vital capacity (VC) and transfer factor (TLCO). Although involvement of the peripheral airways is common, they are poorly represented in current diagnostics. Impulse oscillometry (IOS) and multiple breath washout (MBW) could be promising for assessing peripheral resistance and ventilation heterogeneity. We aimed to evaluate both techniques as compared to conventional lung function testing in ILD. Methods: Body plethysmography, IOS and TLCO determination were performed in 44 participants. Lung clearance index (LCI) was calculated from sulfur hexafluoride MBW. Severity graduation was done according to ATS/ERS recommendations. Results: 21 controls and 23 ILD patients were included (fibrosis n=10, sarcoidosis n=13). LCI was elevated in ILD and increased with restriction severity (ANOVA, p Conclusion: LCI and IOS parameters are elevated in ILD and could provide additional information to conventional lung function testing in initial assessment and follow-up. Further studies should aim at a potential clinical benefit especially in early detection and at a refined graduation.

Background: Assessment of COPD is primarily based on spirometric and clinical parameters with peripheral airways poorly represented in current diagnostics. Impulse oscillometry (IOS) promisingly assessed peripheral resistance. Ventilation heterogeneity could be determined using MBW. Being established in children with cystic fibrosis, little data is available for adults. We aimed to evaluate MBW as compared to conventional lung function testing and IOS in COPD. Methods: Body plethysmography and IOS were performed in 53 participants. Lung clearance index (LCI) and indices of acinar and conductive ventilation heterogeneity (Sacin, Scond) were calculated from MBW. Results: LCI significantly differed between 32 COPD patients (10.9±2.0) and 21 controls (7.3±0.9, p -1 , p -1 , p=0.03). Conclusion: LCI and Sacin are feasible for the determination of ventilation heterogeneity in COPD representing the severity graduation of current diagnostic concepts. Further evaluation should aim at a potential clinical benefit in early detection of obstructive disorders and small airways dysfunction.

Electrical velocimetry (EV) is one of the most recent adaptions of impedance cardiography. Previous studies yielded diverging results identifying several factors negatively influencing accuracy. Although electrode arrangement is suspected to be an influencing factor for impedance cardiography in general, no data for EV is available. We aimed to prospectively assess the influence of electrode position on the accuracy and reproducibility of cardiac output (CO) measurements obtained by EV. Two pairs of standard electrocardiographic electrodes were placed at predefined positions of the thorax in 81 patients. The inter-electrode gap was varied between either 5 or 15 cm by caudal movement of the lowest electrode. Measurements were averaged over 20 s and performed twice at each electrode position. Reference values were determined using cardiac magnetic resonance imaging (CMR). Mean bias was 1.2 ± 1.6 l min(-1) (percentage error 22 ± 28%) between COCMR and COEV at the 5 cm gap significantly improving to 0.5 ± 1.6 l min(-1) (8 ± 28%) when increasing the gap (p 0.0001). The mean difference between repeated measurements was 0.0 ± 0.3 l min(-1) for the 5 cm and 0.1 ± 0.3 l min(-1) for the 15 cm gap, respectively (p = 0.3). The accuracy of EV can be significantly improved when increasing the lower inter-electrode gap still exceeding the Critchley and Critchley recommendations. Therefore, absolute values should not be used interchangeably in clinical routine. As the reproducibility was not negatively affected, serial hemodynamic measurements can be reliably acquired in stable patients when the electrode position remains unchanged.

Background and objective: Endobronchial ultrasound (EBUS) is now widely used in patients with resectable non-small-cell lung cancer to sample mediastinal lymph nodes (LN) for preoperative staging.The aim of this study was to investigate prospectively the utility of six ultrasound criteria to predict malignancy in mediastinal LN. Methods: EBUSwasperformedinpatientswithmediastinal lymphadenopathy irrespective of the underlying disease. The following criteria were expected to predict malignancy: short axis >1 cm, heterogeneous pattern, round shape, distinct margin, absence of a central hilar structure and high blood flow in a LN. A sumscorepredictionmodelformalignancywasbuilt.If morethantwocriteriawerepresent,LNwasclassifiedas high risk for malignancy.Moreover,interrater variability of two blinded investigators was evaluated. Results: Two hundred eighty-one LN in 145 patients were analysed. Forty-four percent of LN were found malignant,10% revealed sarcoidosis,and 10% revealed tuberculosis. Interobserver agreement was very good. Positive predictive value was best for heterogeneity (73%), with a negative predictive value of more than 80%.The sum score resulted in an odds ratio of 15.5 if more than two criteria were positive (P < 0.00001). Conclusions: The assessment of ultrasound criteria during routine EBUS examinations is feasible and reproducible with very good interrater agreement. If less than three of the described criteria are present, a LN has a very low chance of being malignant.The best single criterion to predict malignancy is heterogeneity. The introduction of the sum score of ultrasound criteria could potentially increase diagnostic accuracy.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the non-invasive diagnosis of pulmonary hypertension. This manuscript describes in detail the results and recommendations of the working group which were last updated in October 2011.

Die 2009 veroffentliche Europaischen Leitlinien zur Diagnostik und Therapie der pulmonalen Hypertonie sind nunmehr auch in Deutschland gultig. Die Leitlinien befassen sich eingehend mit der Diagnostik der pulmonalen Hypertonie. Fur die praktische Umsetzung der Europaischen Leitlinien in Deutschland sind jedoch zahlreiche spezifische Gesichtspunkte und neue Daten bedeutsam, die eine ausfuhrliche Kommentierung der Leitlinien und in einigen Punkten eine Aktualisierung notwendig machen. Im Juni 2010 fand in Koln eine Konsensuskonferenz statt, die von den Arbeitsgruppen PH der Deutschen Gesellschaften fur Kardiologie (DGK), Pneumologie (DGP) und Padiatrische Kardiologie (DGPK) organisiert wurde. Die Konferenz befasste sich mit der Umsetzung der Europaischen Leitlinien in Deutschland. Dazu wurden verschiedene Arbeitsgruppen eingesetzt, von denen sich eine gezielt der nicht-invasiven Diagnostik der pulmonalen Hypertonie widmete. Die Ergebnisse und Beschlusse dieser Arbeitsgruppe werden in dem vorliegenden Manuskript detailliert beschrieben. The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update y appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to non-invasive diagnosis of PH. This commentary summarizes the results and recommendations of the working group on treatment of PAH.

Cardiac output (CO) is an important parameter for diagnosis and therapy of heart diseases, but it is still difficult to determine. Innocor, a novel noninvasive inert gas rebreathing (IGR) system, has shown promising results. However, the impact of pulmonary diseases on IGR remains unclear. The aim of the study therefore was to assess the accuracy and reliability of IGR in patients with distinct chronic lung disease. A total of 96 patients were enrolled, including 48 consecutive patients with variant lung diseases (group A) and 48 pair-matched pulmonary healthy patients (group B). CO was measured with cardiac magnetic resonance imaging (CMR) and IGR. Lung function testing was done by spirometry [FEV(1)/FVC (forced expiratory volume in one second/forced vital capacity), VC (vital capacity)] and determination of the diffusing capacity of the lung for carbon monoxide divided by alveolar volume (DLCO/VA). In group A we found a mean CO of 4.7 ± 1.3 L/min by IGR and 4.9 ± 1.2 L/min by CMR. Group B showed a mean CO of 4.8 ± 1.4 L/min by IGR and 5.0 ± 1.3 L/min by CMR. Bland-Altman analysis revealed good correspondence between CMR and IGR, with an average deviation of 0.1 ± 1.0 L/min in group A and 0.1 ± 1.0 L/min in group B (p = 0.99). Multiple regression analysis for the pulmonary parameters did not show a statistically significant impact on the mean bias of CO measurements (FEV(1)/FVC: r = 0.01, p = 0.91; VC: r = -0.2, p = 0.13; and DLCO/VA: r = 0.04, p = 0.82). IGR allows a feasible determination of CO even in patients with lung diseases. The accuracy of the IGR method is not influenced by either pulmonary obstructive and restrictive diseases or a reduced DLCO.

Objectives: Atrial fibrillation (AF) is one of the most frequent heart rhythm disorders. It potentially influences cardiac function and its measurement. Cardiac magnetic resonance imaging (CMR) has become the new gold standard for non-invasive assessment of cardiac output (CO). A novel inert gas rebreathing (IGR) device based on the Fick Principle also proved promising in patients in sinus rhythm (SR). The aim of our study was to compare the agreement of non-invasive CO measurements between CMR and IGR in AF patients. Methods: A total of 68 patients, 34 with AF and 34 pair-matched controls in SR, were included. Results: Bland-Altman analysis showed good agreement between both methods, with an average deviation of 0.2 ±1.2 l/min in the AF group versus 0.3 ±1.0 l/min in the SR group (p = 0.77). IGR demonstrated good agreement for CO between 2.0 and 5.4 l/min. However, in hyperdynamic circulatory conditions (CO >5.5 l/min), the increasing disagreement of IGR and CMR measurements reached statistical significance. Conclusions: Non-invasive CO measurements using CMR and IGR are feasible in patients suffering from AF. Good agreement was found between the two methods in an unselected cohort. Hyperdynamic circulatory conditions can lead to significant measurement differences which, however, do not affect the reproducibility of IGR.

Electromagnetic induction is a powerful technique to study the electrical conductivity of the interior of the Earth and other solar system bodies. Information about the electrical conductivity structure can provide strong constraints on the associated internal composition of planetary bodies. Here we give a review of the basic principles of the electromagnetic induction technique and discuss its application to various bodies of our solar system. We also show that the plasma environment, in which the bodies are embedded, generates in addition to the induced magnetic fields competing plasma magnetic fields. These fields need to be treated appropriately to reliably interpret magnetic field measurements in the vicinity of solar system bodies. Induction measurements are particularly important in the search for liquid water outside of Earth. Magnetic field measurements by the Galileo spacecraft provide strong evidence for a subsurface ocean on Europa and Callisto. The induction technique will provide additional important constraints on the possible subsurface water, when used on future Europa and Ganymede orbiters. It can also be applied to probe Enceladus and Titan with Cassini and future spacecraft.

著者人数：156名, Accepted: 2008-05-27, 資料番号: SA1000998000

Diagnosis of Takotsubo cardiomyopathy (also known as stress cardiomyopathy or acute left ventricular apical ballooning syndrome) can be challenging in patients who are being treated for other diseases in the intensive care unit, because symptoms could erroneously be attributed to the underlying disease or patients may not experience symptoms due to analgesia and sedation. The aim of our study was to assess clinical features of Takotsubo cardiomyopathy occurring in the intensive care unit. Prospective observational study. University hospital. Six consecutive patients diagnosed with Takotsubo cardiomyopathy who were being treated for other diseases in the intensive care unit. None. Sudden hemodynamic deterioration (i.e., sudden hypotension, tachycardia or drop in monitored stroke volume) requiring vasopressor support was the presenting symptom in five of the six patients. Only one patient was able to report angina-like chest pain, all others were unable to experience symptoms due to analgesia and sedation. The electrocardiogram was abnormal in all patients upon diagnosis, demonstrating either ST-segment elevation (n = 2) and/or T-wave inversion (n = 5). Mild elevation of cardiac enzymes disproportionate to the extent of wall motion abnormalities on left ventriculography was present in all patients. All patients survived their acute event. Sudden hemodynamic deterioration requiring vasopressor support and/or ECG abnormalities consisting of ST-segment elevation, ST-segment depression or T-wave inversion may be the presenting symptom of Takotsubo cardiomyopathy in the intensive care unit and should be included in the diagnostic algorithm.

Background Cardiac Output (CO) is an important parameter in the diagnosis and therapy of heart diseases. Inert gas rebreathing (IGR) and continuous wave Doppler ultrasound (CWD) are among the most promising newer techniques aiming at a non-invasive, point of care measurement of CO. A direct comparison of the two methods has not yet been carried out. Methods 63 consecutive patients were included in the study. CO was measured twice with both CWD and IGR to assess inter-method agreement and reproducibility. The statistical comparisons were performed as proposed by Bland and Altman. Results There was a significant correlation between the CO measurements by both methods ( r =0.53, p p =0.13). Conclusion The determination of CO by IGR and CWD revealed a good agreement and reproducibility with a low rate of impossible measurements, suggesting that IGR and CWD can be used interchangeably in the clinical setting.

Non-invasive inert gas rebreathing (IGR) has shown promising results in the determination of pulmonary blood flow. The volume of the rebreathing bag (V bag) is proposed by the system. However, elderly patients or those with severe pulmonary disease may be unable to rebreathe this volume entirely. We evaluated the effect of adapting V bag on the reproducibility of IGR. A total of 270 valid measurements were obtained from 45 patients with obstruction (group A), restriction (group B), and in healthy controls (group C). Two measurements for each of three different V bag of 1,200, 1,700, and 2,200 ml were conducted in the supine position. We found no statistically significant difference of the repeated measurements neither between the different V bag in groups A to C nor between the three groups for identical V bag. There was a weak yet significantly worse coefficient of variation between a V bag of 2,200 ml in group A compared with group C with 2,200 and 1,200 ml, respectively. Intraclass correlation coefficient and repeatability coefficient yielded significantly worse values in group A for a V bag of 2,200 ml compared with healthy controls and lower bag volumes. No difference could be found intraclass nor interclass in groups B and C. V bag can be altered between 1,200 and 2,200 ml in most situations without affecting the reproducibility. Attention has to be paid to extreme volumes in obstructive patients. Nevertheless, V bag should be chosen as large as possible and therefore has to be carefully adapted, particularly in patients with obstruction or restriction.

The present OSS mission continues a long and bright tradition by associating the communities of fundamental physics and planetary sciences in a single mission with ambitious goals in both domains. OSS is an M-class mission to explore the Neptune system almost half a century after flyby of the Voyager 2 spacecraft. Several discoveries were made by Voyager 2, including the Great Dark Spot (which has now disappeared) and Triton's geysers. Voyager 2 revealed the dynamics of Neptune's atmosphere and found four rings and evidence of ring arcs above Neptune. Benefiting from a greatly improved instrumentation, it will result in a striking advance in the study of the farthest planet of the Solar System. Furthermore, OSS will provide a unique opportunity to visit a selected Kuiper Belt object subsequent to the passage of the Neptunian system. It will consolidate the hypothesis of the origin of Triton as a KBO captured by Neptune, and improve our knowledge on the formation of the Solar system. The probe will embark instruments allowing precise tracking of the probe during cruise. It allows to perform the best controlled experiment for testing, in deep space, the General Relativity, on which is based all the models of Solar system formation. OSS is proposed as an international cooperation between ESA and NASA, giving the capability for ESA to launch an M-class mission towards the farthest planet of the Solar system, and to a Kuiper Belt object. The proposed mission profile would allow to deliver a 500 kg class spacecraft. The design of the probe is mainly constrained by the deep space gravity test in order to minimise the perturbation of the accelerometer measurement., 43 pages, 10 figures, Accepted to Experimental Astronomy, Special Issue Cosmic Vision. Revision according to reviewers comments

OBJECTIVE: It is unclear which of the commonly used asthma-specific quality of life (QoL) questionnaires best capture the lived experience of people with asthma. The objective of this study was to explore patients' views on three asthma-specific QoL questionnaires. METHODS: Ten adult individuals with asthma were asked to complete three asthma-specific QoL questionnaires (Standardized Juniper Asthma Quality of Life Questionnaire (AQLQ-J-s), Sydney Asthma Quality of Life Questionnaire (AQLQ-S), and Fragebogen zur Lebensqualitat bei Asthma (FLA)). Interviews were conducted to elicit patients' views on the questionnaires. Interviews were transcribed verbatim and thematic content analysis was performed. RESULTS: Participants spoke about response format and options, missing and redundant/similar content as well as content that was perceived to be irrelevant. A lack of specificity was named for some items, and issues concerning layout were raised. Despite the diversity of views expressed, participants mostly agreed on the ranking of the questionnaires and, overall, favored the AQLQ-S. CONCLUSIONS: Patient involvement highlights shortcomings and strengths of various asthma-specific questionnaires in terms of both format and content. The AQLQ-S was the most positively perceived questionnaire. Future research will need to explore other settings and potentially involve a larger and more diverse sample.

The adipocyte-specific protein adiponectin reveals anti-inflammatory, antioxidant, antiatherosclerotic and vasoprotective effects. This study aims to investigate adiponectin expression in cultured human adipocytes within an inflammatory model and in patients with severe sepsis and evaluates treatment effects of drotrecogin α (activated) (DAA). In an in vitro inflammatory model of adipocyte cell culture, the effect of DAA on adiponectin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction. Supernatants of these adipocytes and serum levels of adiponectin were measured in blood of 104 patients by enzyme-linked immunosorbent assay on days 1, 3, and 5 of severe sepsis. Twenty-six patients were treated with DAA (DAA), 78 patients without DAA (DAA). Stimulation of human adipocytes with tumor necrosis factor α over 6 and 24 h resulted in a significant decrease in adiponectin mRNA transcripts. After 24 h of incubation, adiponectin mRNA expression was significantly upregulated according to applied dosages of DAA at 50 ng/mL and 5 μg/mL (P0.05). Accordingly, adiponectin levels of supernatants of adipocyte culture increased after 24 h (P0.05). DAA patients revealed significantly higher adiponectin serum levels compared with healthy controls (P0.1) and DAA patients (P0.05) at days 1 and 3. On day 5 after 96-h infusion of DAA (24 μg/kg per hour), adiponectin levels significantly increased in DAA patients and equalized toward DAA patients (P0.1). Adiponectin might be involved in the pathogenesis of the systemic inflammatory response during sepsis. Administration of DAA upregulates adiponectin expression under circumstances of systemic inflammation.

Objectives A growing interest in monitoring cardiac output (CO) noninvasively has emerged; however, its determination has been difficult using the standard approaches. The aim of this study was to evaluate the accuracy and precision of pulse contour analysis (PCA) compared with cardiac magnetic resonance imaging (CMR). Design A single-center prospective study. Setting A university hospital. Participants Thirty-nine consecutive stable patients undergoing CMR. Interventions CO was determined twice by PCA using the Nexfin monitoring system (BMEYE BV, Amsterdam, The Netherlands). Measurements were performed after 10 minutes of rest in a stable supine position immediately before or after the CMR examination. Measurements and Main Results There was a mean bias of 0.2 ± 1.9 L/min between CMR and PCA and a reproducibility of 0.2 ± 0.6 L/min for PCA. Between 4.8 and 6.3 L/min (second quartile of COCMR), there was a good agreement (mean bias = −0.2 ± 1.3 L/min). Comparing quartile 1 (−1.3 ± 2.0 L/min) overestimating and quartiles 3 (1.4 ± 0.9 L/min) and 4 (0.9 ± 2.0 L/min) underestimating CO, a statistically significant difference was found. The reproducibility was not affected by the quartile (p = 0.23, analysis of variance), whereas there was a significant difference between the nonoutlier and outlier group when using the Mann-Whitney U test (p = 0.02). Conclusions Noninvasive PCA allows the safe and economic measurement of CO, yet it still has major limitations. Although the agreement with CMR was acceptable, there was a clinically unacceptable variation; absolute values should not be used interchangeably. These results suggest that therapeutic interventions and clinical decisions should not be based on noninvasive PCA measurements at the present time.

Objective To evaluate the impact of coronary CT angiography (coronary CTA) or “triple-rule-out” CT angiography (TRO-CTA) on patient management in the work-up of patients with acute chest pain and an intermediate cardiac risk profile. Materials and methods 100 patients with acute chest pain and an intermediate cardiac risk for acute coronary syndrome (ACS) underwent coronary CTA or TRO-CTA for the evaluation of chest pain. Patients with a high and low cardiac risk profile were not included in this study. All patients with significant coronary stenosis >50% on coronary CTA underwent invasive coronary catheterization (ICC). Important other pathological findings were recorded. All patients had a 90-day follow-up period for major adverse cardiac events (MACE). Results Based on a negative coronary CTA 60 of 100 patients were discharged on the same day. None of the discharged patients showed MACE during the 90-day follow-up. Coronary CTA revealed a coronary stenosis >50% in 19 of 100 patients. ICC confirmed significant coronary stenosis in 17/19 patients. Among the 17 true positive patients, 9 underwent percutaneous coronary intervention with stent implantation, 7 were received intensified medical therapy, and 1 patient underwent coronary artery bypass surgery. A TRO-CTA protocol was performed in 36/100 patients due to elevated d -dimer levels. Pulmonary embolism was present in 5 patients, pleural effusion of unknown etiology in 3 patients, severe right ventricular dysfunction with pericardial effusion in 1 patient, and an incidental bronchial carcinoma was diagnosed in 1 patient. Conclusion Coronary CTA and TRO-CTA allow a rapid and safe discharge in the majority of patients presenting with acute chest pain and an intermediate risk for ACS while at the same time identifies those with significant coronary artery stenosis.

Background The adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C. Methods In an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-). Results Stimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p Conclusions Leptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.

When assessing the function of the cardiovascular system, cardiac output (CO) is a substantial parameter. For its determination, numerous non-invasive techniques have been proposed in the recent years including inert gas rebreathing (IGR) and impedance cardiography (ICG). The aim of our study was to evaluate whether a novel ICG algorithm (electrical velocimetry) and IGR can be used interchangeably in the clinical setting. A total of 120 consecutive stable patients were included resulting in two pairs of repeated non-invasive cardiac output measurements. The mean CO was 5.0 ± 1.2 l/min (range 2.6–8.6 l/min) using IGR and 4.4 ± 1.1 l/min (1.7–7.4 l/min) using ICG, respectively. Bland–Altman analysis revealed an acceptable agreement with a mean bias of 0.6 ± 1.2 l/min. We found a high reproducibility with a mean bias of 0.2 ± 0.7 l/min for IGR and 0.0 ± 0.3 l/min for ICG (p

[1] Titan's atmosphere emits energetic neutral atoms (ENAs), which are being monitored for the first time by the Cassini spacecraft. These ENAs are generated by charge exchange processes of energetic ions with neutrals from Titan's atmosphere. In this work we investigate the morphology of the ENA emission from Titan's atmosphere with a three-dimensional model that calculates the phase space density of the charge exchanging energetic ion population in the vicinity of Titan. With the model ion distribution we calculate the resulting ENA distribution and then generate maps of the ENA emission on a sphere above Titan's atmosphere. We demonstrate that the strongly draped magnetic field lines play an essential role in shaping the ENA morphology. The ENA morphology associated with spatially constant magnetic and electric fields is distinctly different. Observations of ENAs from Titan thus can be used in turn to monitor the electrodynamically complex environment as a whole, which is otherwise only accessible with local measurements along single trajectories.

Background USCOM, a novel continuous wave Doppler (CWD) device, has been introduced for noninvasive determination of cardiac output (CO). The present study aimed to compare the accuracy and reproducibility of the new device, using cardiovascular magnetic resonance imaging (CMR) as the noninvasive gold standard. Methods and Results The CO of 56 consecutive patients was prospectively determined by CWD either before or after CMR imaging. The CWD probe was placed in the suprasternal or supraclavicular notch aiming at the aortic valve. Valid CWD signals could be obtained in 45 patients yielding a CO of 5.3±1.1 L/min (range, 3.0–7.5 L/min) by CMR and 4.7±1.1 L/min by CWD (2.5–8.0 L/min, P = .004), respectively. CWD measurements showed an acceptable agreement with CMR (bias: 0.6±1.1 L/min) and a high reproducibility (bias: 0.1±0.4 L/min). Higher CO and body mass index (BMI) were identified as sources of inaccuracy in univariate analysis. By multivariate analysis, only COCMR was found to be independently associated with larger variation. Estimated diameters of the left ventricular outflow tract (LVOT), a prerequisite for CO measurement by CWD, correlated only weakly with those measured by CMR. Conclusions Continuous wave Doppler is a feasible technique for measuring cardiac function. Although the overall agreement with CMR was acceptable, CWD showed a trend to underestimate CO. The estimated LVOT diameter by CWD is likely to be an important source of error. Nevertheless, the CWD device could be of clinical use especially for detection of intraindividual hemodynamic changes since a high reproducibility could be demonstrated. Copyright © 2010 Wiley Periodicals, Inc.

BACKGROUND: Cardiac output (CO) is an important cardiac parameter, however its determination is difficult in clinical routine. Non-invasive inert gas rebreathing (IGR) measurements yielded promising results in recent studies. It directly measures pulmonary blood flow (PBF) which equals CO in absence of significant pulmonary shunt flow (Q(S)). A reliable shunt correction requiring the haemoglobin concentration (c(Hb)) as only value to be entered manually has been implemented. Therefore, the aim of the study was to evaluate the effect of various approaches to Q(S) correction on the accuracy of IGR. METHODS: Cardiac output determined by cardiac magnetic resonance imaging (CMR) served as reference values. The data was analysed in four groups: PBF without correcting for Q(S) (group A), shunt correction using the patients' individual c(Hb) values (group B), a fixed standard c(Hb) of 14.0 g dl(-1) (group C) and a gender-adapted standard c(Hb) for male (15.0 g dl(-1)) and female (13.5 g dl(-1)) probands each (group D). RESULTS: 147 patients were analysed. Mean CO(CMR) was 5.2 +/- 1.4 l min(-1), mean CO(IGR) was 4.8 +/- 1.3 l min(-1) in group A, 5.1 +/- 1.3 in group B, 5.1 +/- 1.3 l min(-1) in group C and 5.1 +/- 1.4 l min(-1) in group D. The accuracy in group A (mean bias 0.5 +/- 1.1 l min(-1)) was significantly lower as compared to groups B, C and D (0.1 +/- 1.1 l min(-1); P

Background: An easy, noninvasive and accurate technique for measuring cardiac output (CO) would be desirable for the diagnosis and therapy of cardiac diseases. Innocor, a novel inert-gas-rebreathing (IGR) system, has shown promising results in smaller studies. An extensive evaluation in a larger, less homogeneous patient collective is lacking. Methods: We prospectively assessed the accuracy and reproducibility of CO measurements obtained by IGR in 305 consecutive patients as compared to the noninvasive gold standard, cardiovascular magnetic resonance (CMR) imaging. Results: Bland-Altman analysis showed a good correspondence of the two methods for CO measurement with an average deviation of 0.2 ± 1.0 liters/min (mean ± SD) and a good reproducibility with a mean bias of 0.2 ± 0.5 liters/min. The accuracy of the present measurements at rest was significantly better in the physiological range than in higher or lower CO ranges. The error levels set forth by current recommendations were exceeded. Conclusion: The data show that IGR measurements are easy to perform and show good agreement with CMR; however, the technique appears to be less accurate in extreme CO ranges at rest. The clinical importance of the IGR method remains to be proven by further studies.

[1] Time variability of Enceladus' gas plume is deduced from a joint investigation of Cassini spacecraft magnetic field data obtained during the first three flybys E0, E1 and E2 and neutral density measurements during the E2 flyby with a model that describes Enceladus' plasma interaction with individual jets. We infer a total plume content of ∼7 × 1032 H2O molecules corresponding to a mass loss rate of ∼1600 kg/s for the E0 flyby and ∼9 × 1031 H2O molecules corresponding to a mass loss of ∼200 kg/s for the E1 and E2 flybys. The magnetic field measurements also support upstream/downstream changes of the plume activity locations. On the first three Enceladus flybys Cassini did not fly through the densest parts of the plumes, which were a factor of 10–100 times higher at the same altitudes.

The New Horizons (NH) spacecraft observed Io's aurora in eclipse on four occasions during spring 2007. NH Alice ultraviolet spectroscopy and concurrent Hubble Space Telescope ultraviolet imaging in eclipse investigate the relative contribution of volcanoes to Io's atmosphere and its interaction with Jupiter's magnetosphere. Auroral brightness and morphology variations after eclipse ingress and egress reveal changes in the relative contribution of sublimation and volcanic sources to the atmosphere. Brightnesses viewed at different geometries are best explained by a dramatic difference between the dayside and nightside atmospheric density. Far-ultraviolet aurora morphology reveals the influence of plumes on Io's electrodynamic interaction with Jupiter's magnetosphere. Comparisons to detailed simulations of Io's aurora indicate that volcanoes supply 1 to 3% of the dayside atmosphere.

[1] The electromagnetic interaction between Io and Jupiter's magnetic field leads to single or multiple ultraviolet spots near the feet of the Io flux tube. Variations of spot numbers and brightness and of inter-spot distances have been observed to be linked to Io's position in its plasma torus. We have studied the evolution of the Io UV footprints with a time resolution of a few tens of seconds using the Space Telescope Imaging Spectrograph (STIS) in time-tag mode. We present evidence of systematic strong brightness variations of the main spots (up to 50%) with a typical growth time of 1 minute. Additionally, unanticipated simultaneous fluctuations of both primary and secondary spots have also been found in the southern hemisphere. Our findings suggest that the footprint brightness is not only actively controlled by the plasma directly interacting with Io but also by the poorly constrained electron acceleration region between Io and Jupiter.

Lee et al should be commended for showing that non-invasive haemodynamic monitoring using inert gas rebreathing (IGR) might be a valuable tool to detect treatment response in patients with precapillary pulmonary hypertension (PH).1 Even under resting conditions, haemodynamic parameters may be more sensitive than the 6-minute walk distance. This is especially interesting as it may facilitate frequent therapy monitoring. Although pulmonary blood flow (PBF) …

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