Therapeutic Bubbles

Ultrasound contrast agents consist of gas microbubbles (1 – 10 μm) that are coated by a protein, lipid or polymer. In addition to their diagnostic value, microbubbles have great potential as local drug delivery systems. Generally, two methods can be distinguished. The first is co-administration, i.e. the simultaneously administration of drugs and microbubbles where the vibrating microbubbles induce a transient increase in permeability of cell membranes and/or tissues. Elucidating this mechanism was one of the aims of this thesis. We found a direct correlation between vibrating microbubble-induced cell deformation and cell membrane permeability. Microbubbles induced transient pore formation, but also increased endocytosis. Endocytosis contribution was found to be dependent on the molecular size of the drug. Both intracellular calcium and reactive oxygen species were found to play a role in the mechanism of microbubble-induced increase in endothelial layer permeability. Targeted microbubbles could also increase cell membrane permeability, indicating that molecular imaging and drug delivery can be combined. The second class of therapeutic bubbles is the incorporation of a drug in the microbubble. Polymer microbubbles were constructed containing gas and therapeutics. Using ultrasound, the therapeutics were released from the microbubbles and taken up by cells. In addition, these microbubbles were found to induce an increase in endothelial cell membrane permeability as also observed with our co-administration studies. The research described in this thesis aids in understanding how to utilise bubbles for therapy in the most optimal way. However, many technical and pharmaceutical issues still need to be resolved before microbubble-mediated treatments in humans become available. For now, therapeutic bubbles are excitingly vibrant and bursting of great potential

Likelihood diagnostics and Bayesian analysis of a micro-economic disequilibrium model for retail services

In this paper we apply Maximum Likelihood and Bayesian methods to explain differences in floorspace productivity among retail establishments in the grocery trade. The model we develop is a switching model where sales are either supply-determined or demand-determined. Under excess supply the model allows for so-called ‘trading-down’, i.e., an increase in the share of selling area, and, thereby, a decrease in service level. To estimate our model we employ a cross-section of observations on individual shops. We present maximum likelihood results, and also study the shape of the likelihood surface by means of Monte Carlo numerical integration methods. With a uniform prior we obtain marginal posterior density functions both of the parameters of interest and of the average probability of the excess supply regime in the sample. The average probability of excess supply is 0.23, with a standard deviation of 0.06. This shows that, according to our estimates, excess demand is the rule and excess supply the exception in the sample that we analyse

An in vitro proof-of-principle study of sonobactericide

Infective endocarditis (IE) is associated with high morbidity and mortality rates. The predominant bacteria causing IE is Staphylococcus aureus (S. aureus), which can bind to existing thrombi on heart valves and generate vegetations (biofilms). In this in vitro flow study, we evaluated sonobactericide as a novel strategy to treat IE, using ultrasound and an ultrasound contrast agent with or without other therapeutics. We developed a model of IE biofilm using human whole-blood clots infected with patient-derived S. aureus (infected clots). Histology and live-cell imaging revealed a biofilm layer of fibrin-embedded living Staphylococci around a dense erythrocyte core. Infected clots were treated under flow for 30 minutes and degradation was assessed by time-lapse microscopy imaging. Treatments consisted of either continuous plasma flow alone or with different combinations of therapeutics: oxacillin (antibiotic), recombinant tissue plasminogen activator (rt-PA; thrombolytic), intermittent continuous-wave low-frequency ultrasound (120-kHz, 0.44 MPa peak-to-peak pressure), and an ultrasound contrast agent (Definity). Infected clots exposed to the combination of oxacillin, rt-PA, ultrasound, and Definity achieved 99.3 ± 1.7% loss, which was greater than the other treatment arms. Effluent size measurements suggested low likelihood of emboli formation. These results support the continued investigation of sonobactericide as a therapeutic strategy for IE

Ultrasound-triggered local release of lipophilic drugs from a novel polymeric ultrasound contrast agent

The advantage of ultrasound contrast agents (UCAs) as drug delivery systems is the ability to non-invasively control the local and triggered release of a drug or gene. In this study we designed and characterized a novel UCA-based drug delivery system, based on polymer-shelled microcapsules filled with a mixture of gas and oil, for the local delivery of lipophilic drugs

Prospects for local co-governance

British local authorities and their partners are increasingly developing new ways of working together with local communities. The nature of this co-working, however, is complex, multi-faceted and little understood. This article argues for greater clarity of thinking on the topic, by analysing this co-working as a form of political co-governance, and drawing attention in particular to issues of scale and democracy. Using evidence from a study of 43 local authority areas, 16 authorities are identified where co-governance is practised, following three main types of approach: service-influencing, service-delivering and parish council developing. It is concluded that strengthening political co-governance is essential for a healthy democracy

Acoustic Characterization of a Vessel-on-a-Chip Microfluidic System for Ultrasound-Mediated Drug Delivery

Ultrasound in the presence of gas-filled microbubbles can be used to enhance local uptake of drugs and genes. To study the drug delivery potential and its underlying physical and biological mechanisms, an in vitro vessel model should ideally include 3D cell culture, perfusion flow, and membranefree soft boundaries. Here, we propose an organ-on-a-chip microfluidic platform to study ultrasound-mediated drug delivery: the OrganoPlate. The acoustic propagation into the OrganoPlate was determined to assess the feasibility of controlled microbubble actuation, which is required to study the microbubble-cell interaction for drug delivery. The pressure field in the OrganoPlate was characterized non-invasively by studying experimentally the well-known response of microbubbles and by simulating the acoustic wave propagation in the system. Microbubble dynamics in the OrganoPlate were recorded with the Brandaris 128 ultrahigh speed camera (17 Mfps) and a control experiment was performed in an OptiCell, an in vitro monolayer cell culture chamber that is conventionally used to study ultrasound-mediated d

Very different performance of the power Doppler modalities of several ultrasound machines ascertained by a microvessel flow phantom

Introduction: In many patients with rheumatoid arthritis (RA) subclinical disease activity can be detected with ultrasound (US), especially using power Doppler US (PDUS). However, PDUS may be highly dependent on the type of machine. This could create problems both in clinical trials and in daily clinical practice. To clarify how the PDUS signal differs between machines we created a microvessel flow phantom.Methods: The flow phantom contained three microvessels (150, 1000, 2000 microns). A syringe pump was used to generate flows. Five US machines were used. Settings were optimised to assess the lowest detectable flow for each US machine.Results: The minimal detectable flow velocities showed very large differences between the machines. Only two of the machines may be able to detect the very low flows in the capillaries of inflamed joints. There was no clear relation with price. One of the lower-end machines actually performed best in all three vessel sizes.Conclusions: We created a flow phantom to test the sensitivity of US machines to very low flows in small vessels. The sensitivity of the power Doppler modalities of 5 different machines was very different. The differences found between the machines are probably caused by fundamental differences in processing of the PD signal or internal settings inaccessible to users. Machines considered for PDUS assessment of RA patients should be tested using a flow phantom similar to ours. Within studies, only a single machine type should be used

Disturbance and Predictability of Flowering Patterns in Bird-Pollinated Cloud Forest Plants

The distribution and flowering patterns of hummingbird—pollinated plants were compared from July 1981 to June 1983 in three patch types in cloud forest at Monteverde, Costa Rica. Study plots were: (1) four recent, large (1100—2500 m2) disturbances ("cutovers") produced by cutting vegetation, (2) six recent, smaller (200—600 m2) disturbances caused by treefalls, and (3) four plots (1600—1800 m2) of canopied forest. Based on published literature dealing with communities that characterize different regimes of disturbance, we tested one assumption and two hypotheses. Assumption: Plant species composition differs among the three patch types. Hypothesis 1: Phenotypic specialization by plants for co—evolved interactions with hummingbirds will be lowest in large gaps, highest in forest, and intermediate in treefalls. Hypothesis 2: Predictability of flowering phenologies and nectar production will be lowest in large gaps, highest in forest, intermediate in treefalls. Neither the assumption nor the hypotheses were supported by the results. The patch mosaic in this cloud forest was not associated with major differences in species composition of bird—pollinated plants. Most species studied were self—compatible. Most abundant in cutovers were species with long corollas, relatively specialized for attracting long—billed hummingbirds. Species with short corollas, which can be visited by many hummingbird species and some insects, were most abundant in treefalls and forest. Variation in phenological patterns showed no consistent trends among patch types. Predictability of flower and nectar production tended to be greatest in treefalls, which are foci of concentrated flowering activity by all species. Discrepancies between our results and previous studies can be ascribed to two facts. (1) Much of the literature dealing with ecological consequences of disturbance has dealt with large—scale anthropogenic disturbances such as old fields of the eastern USA, whereas we studied small, natural, or quasi—natural disturbances. (2) Studies of forest disturbance have focused on the tree layer, whereas we studied the understory herbs, shrubs, and epiphytes. Natural disturbance usually involves death and replacement of one or more trees, whereas individuals of other life forms may persist through the disturbance

Comparing the response modulation hypothesis and the integrated emotions system theory: The role of top-down attention in psychopathy

ERC advanced grant; TUBITAK-BIDEB visiting scientist gran

High Frame Rate Volumetric Imaging of Microbubbles Using a Sparse Array and Spatial Coherence Beamforming

Volumetric ultrasound imaging of blood flow with microbubbles enables a more complete visualization of the microvasculature. Sparse arrays are ideal candidates to perform volumetric imaging at reduced manufacturing complexity and cable count. However, due to the small number of transducer elements, sparse arrays often come with high clutter levels, especially when wide beams are transmitted to increase the frame rate. In this study, we demonstrate with a prototype sparse array probe and a diverging wave transmission strategy, that a uniform transmission field can be achieved. With the implementation of a spatial coherence beamformer, the background clutter signal can be effectively suppressed, leading to a signal to background ratio improvement of 25 dB. With this approach, we demonstrate the volumetric visualization of single microbubbles in a tissue-mimicking phantom as well as vasculature mapping in a live chicken embryo chorioallantoic membrane