Background Platelet aggregation at sites of vascular injury is essential for normal hemostasis, but may also cause pathologic vessel occlusion. Rho GTPases are molecular switches that regulate essential cellular processes, and they have pivotal functions in the cardiovascular system. Rac1 is an important regulator of platelet cytoskeletal reorganization, and contributes to platelet activation. Rac1 inhibitors are thought to be beneficial in a wide range of therapeutic settings, and have therefore been tested in vivo for a variety of disorders. Two small‐molecule inhibitors, NSC23766 and EHT1864, have been characterized in different cell types, demonstrating high specificity for Rac1 and Rac, respectively. Objectives To analyze the specificity of NSC23766 and EHT1864. Methods Platelet function was assessed in mouse wild‐type and Rac1‐deficient platelets by the use of flow cytometric analysis of cellular activation and aggregometry. Platelet spreading was analyzed with differential interference contrast microscopy, and activation of effector molecules was analyzed with biochemical approaches. Results NSC23766 and EHT1864 showed strong and distinct Rac1‐independent effects at 100 μm in platelet function tests. Both inhibitors induced Rac1‐specific inhibition of platelet spreading, but also markedly impaired agonist‐induced activation of Rac1^−/− platelets. Furthermore, glycoprotein Ib‐mediated signaling was dramatically inhibited by NSC23766 in both wild‐type and Rac1‐deficient platelets. Importantly, these inhibitors directly affected the activation of the Rac1 effectors p21‐activated kinase (PAK)1 and PAK2. Conclusions Our results reveal critical off‐target effects of NSC23766 and EHT1864 at 100 μm in mammalian cells, raising questions about their utility as specific Rac1/Rac inhibitors in biochemical studies at these concentrations and possibly as therapeutic agents.

Functional analysis of three-dimensional ultrashort echo time MRI in the lungs can evaluate ventilation inhomogeneity and hyperinflation in patients with cystic fibrosis. Background In cystic fibrosis (CF), recurrent imaging and pulmonary function tests (PFTs) are needed for the assessment of lung function during disease management. Purpose To assess the clinical fe...

T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T. Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences. T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19% lower and ShMOLLI T1 times 25% lower compared to SASHA. Native blood T1 times from MOLLI were 13% lower than SASHA, while post-contrast MOLLI T1-times were only 5% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences. Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values.

Purpose: Cardiac MRI represents the gold standard to determine myocardial function. However, the current clinical standard protocol, a segmented Cartesian acquisition, is time‐consuming and can lead to compromised image quality in the case of arrhythmia or dyspnea. In this article, a machine learning–based reconstruction of undersampled spiral k‐space data is presented to enable free breathing real‐time cardiac MRI with good image quality and short reconstruction times.Methods: Data were acquired in free breathing with a 2D spiral trajectory corrected by the gradient system transfer function. Undersampled data were reconstructed by a variational network (VN), which was specifically adapted to the non‐Cartesian sampling pattern. The network was trained with data from 11 subjects. Subsequently, the imaging technique was validated in 14 subjects by quantifying the difference to a segmented reference acquisition, an expert reader study, and by comparing derived volumes and functional parameters with values obtained using the current clinical gold standard.Results: The scan time for the entire heart was below 1 min. The VN reconstructed data in about 0.9 s per image, which is considerably shorter than conventional model‐based approaches. The VN furthermore performed better than a U‐Net and not inferior to a low‐rank plus sparse model in terms of achieved image quality. Functional parameters agreed, on average, with reference data.Conclusions: The proposed VN method enables real‐time cardiac imaging with both high spatial and temporal resolution in free breathing and with short reconstruction time.

Purpose Segmented Cartesian acquisition in breath hold represents the current gold standard for cardiac functional MRI. However, it is also associated with long imaging times and severe restrictions in arrhythmic or dyspneic patients. Therefore, we introduce a real‐time imaging technique based on a spoiled gradient‐echo sequence with undersampled spiral k‐space trajectories corrected by a gradient pre‐emphasis. Methods A fully automatic gradient waveform pre‐emphasis based on the gradient system transfer function was implemented to compensate for gradient inaccuracies, to optimize fast double‐oblique spiral MRI. The framework was tested in a phantom study and subsequently transferred to compressed sensing–accelerated cardiac functional MRI in real time. Spiral acquisitions during breath hold and free breathing were compared with this reference method for healthy subjects (N = 7) as well as patients (N = 2) diagnosed with heart failure and arrhythmia. Left‐ventricular volumes and ejection fractions were determined and analyzed using a Wilcoxon signed‐rank test. Results The pre‐emphasis successfully reduced typical artifacts caused by k‐space misregistrations. Dynamic cardiac imaging was possible in real time (temporal resolution < 50 ms) with high spatial resolution (1.34 × 1.34 mm²), resulting in a total scan time of less than 50 seconds for whole heart coverage. Comparable image quality, as well as similar left‐ventricular volumes and ejection fractions, were observed for the accelerated and the reference method. Conclusion The proposed technique enables high‐resolution real‐time cardiac MRI with no need for breath holds and electrocardiogram gating, shortening the duration of an entire functional cardiac exam to less than 1 minute.