Quantitative biodistribution and pharmacokinetics of multimodal gadolinium-based nanoparticles for lungs using ultrashort TE MRI

Objective

To study the biodistribution and lung pharmacokinetics of tracheally administered gadolinium-based contrast agents [gadoteric acid and multimodal ultra-small rigid platforms (USRPs)], to validate their pharmacokinetics against optical imaging of fluorescent USRPs, and to test their short-term toxicity.

Materials and methods

Ultrashort echo-time (UTE) lung proton magnetic resonance imaging (MRI) was performed at 4.7-Tesla (T) after the intratracheal instillation of different concentrations of contrast agent solutions in mice. Pharmacokinetic models were implemented on the absolute concentration calculated from the MRI signal enhancement measurements. Fluorescent USRPs were used to obtain optical images with the same protocol. Bronchoalveolar lavage inflammatory cell count and serum creatinine measurement were performed on four groups of instilled mice (sham, saline, USRPs, lipopolysaccharide).

Results

MR and optical imaging showed similar kinetics of the USRPs, passing from the airways to the lung tissue and to the kidneys, with negligible hepatic clearance. No significant increase of lung and renal inflammation markers were observed in USRP-instilled animals.

Conclusion

A T ₁-weighted radial UTE sequence was found to be valuable in quantitatively monitoring the biodistribution and pharmacokinetics of nanoparticles in the lungs of mice. The observed favorable pharmacokinetics, which was validated by fluorescence imaging, ensures the negligible toxicity of the nanoprobes, making the USRPs and the developed protocol good candidates for applications on selected lung diseases.     

Model dependency of multivariate autoregressive spectral analysis

A combination of simulations and experimental data analysis has been used to demonstrate that, because cardiovascular control represents a complex linking of input and output parameters, interpreting the variability of individual parameters such as heart rate and arterial pressure virtually requires the use of techniques that quantify control by relating these inputs and outputs. Transfer functions represent appropriate techniques for this purpose. Further, despite the complexities of in vivo physiological control, many of the control elements can be well characterized by only taking into account single inputs and outputs and using a bivariate AR model. However, occasionally when two control systems have a strong and simultaneous influence on a single output parameter, such as arterial pressure and respiratory activity on RR interval, an expansion of the model to the general multivariate case may be required for a complete interpretation. Finally, although not fully demonstrated here, because of the closed-loop nature of cardiovascular control it is likely that algorithms that include causality to account for this characteristic, such as the AR formulation, will most accurately identify the transfer relations     

Design considerations for fractional-slot winding configurations of synchronous machines

This paper presents some design considerations for synchronous machines characterized by a fractional number of slots per pole per phase. The main advantage of this configuration is a smooth torque, which is due to the elimination of periodicity between slots and poles. A second advantage is a higher fault-tolerant capability, making the machine able to work even in faulty conditions. However, the fractional-slot configuration presents a high content of MMF harmonics that may cause an unbalanced saturation and thus an unbearable torque ripple. A method to design fractional-slot machines is illustrated in this paper, including double-layer and single-layer windings. The analytical computation is extended to determine the harmonics of MMF distribution. Their effect is highlighted in isotropic as well as anisotropic machines. Finally, some considerations are reported to avoid unsuitable configurations.     

Developing wearable bio-feedback systems: a general-purpose platform

Microprocessors, even those in PocketPCs, have adequate power for many real-time biofeedback applications for disabled people. This power allows design of portable or wearable devices that are smaller and lighter, and that have longer battery life compared to notebook-based systems. In this paper, we discuss a general-purpose hardware/software solution based on industrial or consumer devices and a C++ framework. Its flexibility and modularity make it adaptable to a wide range of situations. Moreover, its design minimizes system requirements and programming effort, thus allowing efficient systems to be built quickly and easily. Our design has been used to build two brain computer interface systems that were easily ported from the Win32 platform.     

The use of EEG modifications due to motor imagery for brain-computer interfaces

The opening of a communication channel between brain and computer [brain-computer interface (BCI)] is possible by using changes in electroencephalogram (EEG) power spectra related to the imagination of movements. In this paper, we present results obtained by recording EEG during an upper limb motor imagery task in a total of 18 subjects by using low-resolution surface Laplacian, different linear and quadratic classifiers, as well as a variable number of scalp electrodes, from 2 to 26. The results (variable correct classification rate of mental imagery between 75% and 95%) suggest that it is possible to recognize quite reliably ongoing mental movement imagery for BCI applications.     

Process noise covariance estimation via stochastic approximation

Kalman filtering for linear systems is known to provide the minimum variance estimation error, under the assumption that the model dynamics is known. While many system identification tools are available for computing the system matrices from experimental data, estimating the statistics of the output and process noises is still an open problem. Correlation-based approaches are very fast and sufficiently accurate, but there are typically restrictions on the number of noise covariance elements that can be estimated. On the other hand, maximum likelihood methods estimate all elements with high accuracy, but they are computationally expensive, and they require the use of external optimization solvers. In this paper, we propose an alternative solution, tailored for process noise covariance estimation and based on stochastic approximation and gradient-free optimization, that provides a good trade-off in terms of performance and computational load, and is also easy to implement. The effectiveness of the method as compared to the state of the art is shown on a number of recently proposed benchmark examples.     

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.     

Transient and steady states of Gd2Zr2O7 and 2ZrO2∙Y2O3 (ss) interactions with calcium magnesium aluminium silicates

Reactions between calcium magnesium aluminium silicates (CMAS) and Gd₂Zr₂O₇ or 2ZrO₂?Y₂O₃ (ss) are investigated within a temperature range of 1200–1300 °C and for durations of 1 h–100 h. The evolution of CMAS penetration depth in Gd₂Zr₂O₇ and 2ZrO₂?Y₂O₃ (ss) pellets varies considerably depending on the interaction time. A quantitative analysis of the nature and composition of phases observed in stationary conditions (powder/powder interaction) is performed by SEM-FEG coupled with WDS analyses using micro-agglomerated nanoparticles of Gd₂Zr₂O₇ and 2ZrO₂?Y₂O₃. Faster kinetics of the gadolinium-based system are illustrated through an analysis of the morphology of the reaction area and of the resulting CMAS tightness of reaction products. The compositions and quantities of reaction products observed at equilibrium are very similar for the two systems, but transient states are significantly different.     

Microwave heating controlled reactive melt infiltration for graphite-Si-SiC ceramics manufacturing

In this work, we investigated a procedure which exploits microwave ovens to produce SiC- based components by reactive melt infiltration of silicon into graphite preforms. The employed oven is designed to grant optical access to the sample surface, which allows to measure its temperature evolution though a noncontact pyrometer. This signal was used as a feedback to control the power provided to the preform and as an experimental output whose analysis provides insight into the reaction mechanism. Specifically, it is found that complete infiltration is achieved much before the end of the reaction. The latter is not fully self-sustained as the global reaction rate continuously decreases with time until it is no more able to keep the temperature above the silicon solidification value. At that point, the reaction stops. The analysis of the processed samples proved that this procedure allows producing fully infiltrated samples without material failure by adjusting the heat provided during the infiltration stage rather than by tuning the preform structure and composition, which is the usual approach. The proposed method is less time and energy consuming than the standard one.