Cardiovascular and Thoracic Imaging: Trends, Perspectives and Prospects

Radiology is evolving at a fast pace, and the specific field of cardiovascular and thoracic imaging is no stranger to that trend. While it could, at first, seem unusual to gather these two specialties in a common Issue, the very fact that many of us are trained and exercise in both is more than a hint to the common grounds these fields are sharing. From the ever-increasing role of artificial intelligence in the reconstruction, segmentation, and analysis of images to the quest of functionality derived from anatomy, their interplay is big, and one innovation developed with the former in mind could prove useful for the latter. If the coronavirus disease 2019 (COVID-19) pandemic has shed light on the decisive diagnostic role of chest CT and, to a lesser extent, cardiac MR, one must not forget the major advances and extensive researches made possible in other areas by these techniques in the past years. With this Issue, we aim at encouraging and wish to bring to light state-of-the-art reviews, novel original researches, and ongoing discussions on the multiple aspects of cardiovascular and chest imaging

The pursuit of mechanistic insights underpinning calcium-dependent inactivation of L-type calcium channels: All roads lead to calmodulin

L-type calcium channels (LTCCs) are critical conduits for Ca2+ entry into many excitable cells. In ventricular myocytes, they are responsible for shaping the action potential and triggering Ca2+ release from the sarcoplasmic reticulum leading to myocyte contraction. In the brain, these channels are vital for excitation-transcription coupling, synaptic plasticity, and neuronal firing. To perform their functions properly LTCCs employed two principal forms of feedback regulation which include voltage-dependent inactivation (VDI) and Ca2+-dependent inactivation (CDI). Disruptions in either of these two processes were linked to multiple disorders. For example, mutations in a Ca2+ sensor calmodulin (CaM), a known mediator of CDI, have been associated with long-QT syndrome (LQTS). Patients afflicted with these mutations (calmodulinopathies) suffer from life-threatening arrhythmias, refractory to conventional treatments. First, we dissected the mechanistic underpinnings of the LQTS form of calmodulinopathies. We found that disruption of CDI of CaV1.2 was a major culprit behind this disease. Leveraging off this knowledge, we created a customizable therapy for patients suffering from this group of diseases. Moreover, we investigated mechanisms underlying an autism-associated mutation A760G in CaV1.3 channels. Interestingly, this mutation disrupts both VDI and CDI of CaV1.3 which enables us to explore the intimate interplay between VDI and CDI. The knowledge gained from studying these two diseases extend beyond facilitation of therapy development and prove to be valuable in further our understanding in LTCC regulation under a physiologic state. Next, we utilized an in silico approach to complement our in vitro disease-based models of LTCC regulations. Although it is well known that each lobe of CaM is capable of responding spatially distinct Ca2+ sources, most CDI models fail to capture this unique property of CaM. Therefore, we developed the first kinetic model of CDI which truly captured the bi-lobal nature of CaM. From this model, we were able to gain deeper insight into the extent of interaction between the two lobes of CaM and explained the pathophysiology behind the LTQS form of calmodulinopathies. Once incorporated into a whole-cell or tissue level model, this novel CDI model could be an invaluable asset in understanding of both physiological and pathological states of the overall cardiac and neuronal electrical activities. Lastly, we developed an animal model as a new tool to investigate regulations of cardiac LTCCs in situ. Understanding of these channels’ modulation with high fidelity relies on examining LTCCs in their native environment with intact interacting proteins. Thus, such studies would benefit from genetic manipulation of endogenous LTCCs and their binding partners which often proves cumbersome in mammalian models. We have identified Drosophila as an alternative model to study LTCC regulation. Not only is Drosophila genetically pliable, but it also possesses conserved Ca2+ channels in its cardiomyocytes. Thus, this model may serve as a robust and effective platform for studying in situ LTCC regulation. In all, we utilized multiple approaches to dissect the mechanistic underpinnings of VDI and CDI modulation of LTCCs. We wish that this knowledge could help propel further scientific understanding of these channels’ regulations and brought hope to those suffering from dysregulations of these processes

Strategies and Devices for Improving Respiratory Drug Delivery to Infants and Children with Cystic Fibrosis

Cystic Fibrosis (CF) is a degenerative disease, which causes thickening of the airway surface liquid and reduced mucociliary clearance, which provides an ideal habitat for bacterial infections. Early treatment of CF in children can prevent chronic infection, improve quality of life, and increase life expectancy. The most predominant bacteria found in CF-diseased lungs is Pseudomonas aeruginosa (Pa), which can be treated with inhaled tobramycin. Excipient enhanced growth (EEG) powder formulations are well suited for administering tobramycin to children, as the EEG approach provides minimal upper airway loss and targeted drug delivery. This method uses an initially small aerosol for high extrathroacic transmission, and includes hygroscopic excipients within the formulation that absorb moisture from the humid airways and increase lung retention of the aerosol. The overarching goal of this work was to develop delivery systems and strategies for improving respiratory drug delivery to children with CF, which was based on insights from computational fluid dynamics (CFD) simulations and in vitro models. The studies presented in this dissertation have three distinct and sequential phases: (i) CFD methods development; (ii) respiratory device design and optimization; and (iii) complete-airway modeling for aerosol delivery strategy development. The methods development phase produced meshing and solution guidelines that were computationally-efficient, accurate, and validated based on in vitro data. Results showed that the two-equation k-ω model, with near-wall corrections, was capable of matching experimental data across a range of Reynolds numbers and particle sizes that are specific to respiratory drug delivery. The guidelines also provided comparable accuracy to the more complex Large Eddy Simulation (LES) model, while providing multiple order-of-magnitude savings in computational time. The device optimization phase developed a highly efficient delivery system for tobramycin administration to pediatric CF patients. Correlations were developed, based on flow field quantities, that were predictive of aerosolization performance and depositional loss. Successful a priori validation with experimental testing highlighted the predictive capabilities of the correlations and CFD model accuracy. The best-case delivery system demonstrated an aerosol size of approximately 1.5 µm and expected lung dose of greater than 75% of loaded dose, which is a marked improvement compared to commercial devices. The delivery strategy development phase identified optimal EEG aerosol properties that better unify drug surface concentration. These studies present numerical models of a tobramycin EEG powder formulation for the first time, and provide the first instance of a complete-airway CFD model evaluating pediatric CF lungs. Results show that EEG aerosols are capable of delivering the drug above the minimum inhibitory concentration in all airway regions, reducing regional dose variability, and targeting the lower airways where infection is more predominant. In conclusion, results from this dissertation demonstrate: (i) accurate and efficient CFD models of respiratory drug delivery; (ii) optimized designs for respiratory delivery systems; and (iii) optimal delivery strategies for inhaled tobramycin to pediatric patients with CF

Elucidation of Emergent Regional Mechanisms of Heart Muscle Dysfunction in the Mouse Model of Duchenne Muscular Dystrophy

Cardiac dysfunction is a primary cause of mortality in Duchenne Muscular Dystrophy (DMD), potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here, we elucidate, for the first time, loci- and age-dependencies between calcium mishandling and myocardial sheet function as a manifestation of dystrophin-deficient cardiomyopathy. We also map calcium transients to illustrate the regional dependence of ion flux disturbances in the dystrophin-deficient (mdx) mouse heart. Furthermore, we elucidate abnormalities in autophagic processes that can be corrected with nanoparticle therapeutics delivering rapamycin to heart tissues to improve ventricular function in affected older mice with incipient cardiomyopathy. We conclude that the rapid reversibility of functional defects by reducing cytosolic calcium or by impacting impaired autophagy points to the significance of regional mechanical factors in the progression of the disease

Mechanisms of anthracycline-induced dysfunction of ca2+ handling proteins in the heart

Anthracyclines, such as doxorubicin and daunorubicin, are powerful chemotherapy agents whose use is limited due to the onset of potentially fatal cardiac side effects which include arrhythmogenesis and heart failure. Several proteins important in intracellular Ca2+ signalling have been identified as drug binding targets, including the ryanodine receptor Ca2+ release channel (RyR2), the Ca2+ binding protein calsequestrin (CSQ2) and the Sarco/Endoplasmic Reticulum Ca-ATPase (SERCA2A). The drug metabolites are believed to be important in the devastating cardiac effects of anthracyclines but their actions have been poorly characterized. Previous work showed that daunorubicin modulates RyR2 and that its effects were attributable to ligand binding and thiol oxidation. The functional effect of doxorubicin and its metabolite, doxorubicinol on RyR2 was assessed by adding clinically relevant drug concentrations to single RyR2 channels in lipid bilayers. Anthracyclines caused biphasic modulation of RyR2 where there was an increase in channel activity followed by an inhibitory phase. RyR2 channel activation, but not inhibition, could be reversed by drug washout, typical of a ligand binding effect. This was supported by affinity chromatography experiments showing that doxorubicin and doxorubicinol bind to RyR2. Conversely, the irreversible nature of the inhibitory effect suggested a non-ligand binding effect. Treatment with anthracyclines reduced the number of thiols on RyR2, indicative of a drug-induced thiol-modification such as oxidation. Together, these results support the earlier hypothesis that activation of RyR2 by anthracyclines is due to ligand binding, while the inhibitory effect is due to direct thiol oxidation. In addition to modulating RyR2, doxorubicinol was found to alter other aspects of SR Ca2+ handling. For the first time, the effect of doxorubicinol on the luminal Ca2+ sensitivity of RyR2 channels has been assessed. Doxorubicinol abolished the response of RyR2 to changes in luminal Ca2+. Additional experiments revealed that the abolition of luminal Ca2+ sensing was due to an interaction between doxorubicinol and CSQ2. Furthermore, in SR vesicles, a decrease in the Ca2+ uptake rate showed that doxorubicinol inhibits the function of SERCA2A. This effect could be prevented by pre-treatment with the thiol protective agent dithiothreitol, indicating that doxorubicinol's inhibition of SERCA2A was due to thiol oxidation. Hence doxorubicinol causes substantial dysfunction of SR Ca2+ handling proteins, affecting both Ca2+ release and Ca2+ uptake pathways. To determine the effects of doxorubicinol in an intact cell, cardiomyocytes were isolated from adult mouse hearts and loaded with the Ca2+ indicator Fluo-4. Pre-treatment with doxorubicinol reduced cytoplasmic Ca2+ transients, depleted SR load and inhibited SERCA2A and the Na+- Ca2+ exchanger. Furthermore, doxorubicinol-treated myocytes exhibited more spontaneous Ca2+ release events and had a higher resting Ca2+ concentration. These effects resulted in an overall impairment in contractile function. This project provides novel insight into cellular mechanisms of anthracyclines and is the most thorough characterization of the effects of these drugs on cardiomyocyte Ca2+ handling to date. The results suggest that by targeting multiple Ca2+ handling proteins, anthracyclines severely disturb cardiomyocyte Ca2+ homeostasis and that these effects may have an important role in the onset of anthracycline-mediated arrhythmia and heart failure

Preparation, Physico-Chemical Properties and Biomedical Applications of Nanoparticles

Nowadays, the impact of nanotechnology on applications in medicine and biomedical sciences has broader societal and economic effects, enhancing awareness of the business, regulatory, and administrative aspects of medical applications. The selected papers included in the present Special Issue gives readers a critical, balanced and realistic evaluation of existing nanomedicine developments and future prospects, allowing practitioners to plan and make decisions.The topics of this book covers the use of nanoparticles and nanotechnology in medical applications including biomaterials for tissue regeneration, diagnosis and monitoring, surgery, prosthetics, drug delivery systems, nanocarriers, and wound dressing. I would like to express my gratitude to all contributors to this issue, who have given so much of their time and effort to help create this collection of high quality papers

Queensland University of Technology: Handbook 2018

The Queensland University of Technology handbook gives an outline of the faculties and subject offerings available that were offered by QUT

Toxicological profile for Di(2-Ethylhexyl)Phthalate (DEHP)

Version HistoryDate DescriptionJanuary 2022 Final toxicological profile releasedDecember 2019 Draft for public comment toxicological profile released Final toxicological profile releasedSeptember 2002 Final toxicological profile releasedApril 1993 Final toxicological profile releasedJune 1989 Final toxicological profile releasedtp9.pdf20221085

Towards unmasking the true employee in South Africa’s contemporary work environment: the perennial problem of labour law

The enormously intricate task of unmasking the true employee in contemporary work environment reveals the dilemmas and complexities embedded in the beguilingly simple but intractable question: who is an employee? The hallmarks of a true employee are shaded in modern work environment given that the actual differences between the categories of “employee” and “independent contractor” are diminishing. The conception of self-employment that links being self-employed inextricably with entrepreneurship, ownership, and autonomy has more to do with ideology than reality. In addressing the opacities of form engendered by “Work on demand via app” and the “Uberisation of work”, the study also attends to the significant and neglected component of labour law’s traditional dilemma. Put simply, how the law identifies an “employer” as a counterparty with an “employee”. Certain features of modern business organisation such as vertical disintegration of production, and their link to the rise of precarious employment underscore the extent to which the concept of employer plays a central role in defining the contours of labour protection. The problems of precarity are deep-seated, long-term and even escalating, especially in compelled and dependent self-employment. Re-appraisal South Africa’s black box of precarious self-employment through the lens of Canadian dependent contractor jurisprudence points to key limitations that should be addressed for a more robust and effective vision of labour regulation. If the definition of “employee” in section 213 of the Labour Relations Act 66 of 1995 is amended to redefine an “employee” to include a “dependent contractor”, this will represent a leap forward in tackling the interlinked problems of disguised employment and precarious self-employment. This statutory redefinition of the employee serves two purposes. First, the dependent contractor category solves the broader challenge for labour regulation of how to extend protection to persons who have some of the trappings of the independent contractor, but, in reality, are in a position of i ii economic dependence, resembling that of an employee. In essence, the intermediate category recognises that, as a matter of fairness persons in economic positions that are closely analogous should be given the same legislative treatment. The second purpose, and one no less important, is to fill in the missing piece of the puzzle in the judicially endorsed three-tiered SITA test for identifying employment relationship. If the dependent contractor category is adopted, the lacuna in the threefold SITA test that has so far escaped scholarly, judicial and legislative will be resolved. In this regard, the study contributes to a line of legal scholarship that has tracked the regulatory trajectory for reforming South Africa’s labour laws. It is hoped that this thesis will provoke a sustained, and more curious engagement with the complexities and capacities of labour regulatio