Enhanced ultrasound transmission through the human skull using shear mode conversion

A new transskull propagation technique, which deliberately induces a shear mode in the skull bone, is investigated. Incident waves beyond Snell's critical angle experience a mode conversion from an incident longitudinal wave into a shear wave in the bone layers and then back to a longitudinal wave in the brain. The skull's shear speed provides a better impedance match, less refraction, and less phase alteration than its longitudinal counterpart. Therefore, the idea of utilizing a shear wave for focusing ultrasound in the brain is examined. Demonstrations of the phenomena, and numerical predictions are first studied with plastic phantoms and then using an ex vivo human skull. It is shown that at a frequency of 0.74 MHz the transskull shear method produces an amplitude on the order of--and sometimes higher than--longitudinal propagation. Furthermore, since the shear wave experiences a reduced overall phase shift, this indicates that it is plausible for an existing noninvasive transskull focusing method [Clement, Phys. Med. Biol. 47(8), 1219-1236 (2002)] to be simplified and extended to a larger region in the brain.     

Forced linear oscillations of microbubbles in blood capillaries

A theoretical investigation of the forced linear oscillations of a gas microbubble in a blood capillary, whose radius is comparable in size to the bubble radius is presented. The natural frequency of oscillation, the thermal and viscous damping coefficients, the amplitude resonance, the energy resonance, as well as the average energy absorbed by the system, bubble plus vessel, have been computed for different kinds of gas microbubbles, containing air, octafluropropane, and perflurobutane as a function of the bubble radius and applied frequency. It has been found that the bubble behavior is isothermal at low frequencies and for small bubbles and between isothermal and adiabatic for larger bubbles and higher frequencies, with the viscous damping dominating over the thermal damping. Furthermore, the width of the energy resonance is strongly dependent on the bubble size and the natural frequency of oscillation is affected by the presence of the vessel wall and position of the bubble in the vessel. Therefore, the presence of the blood vessel affects the way in which the bubble absorbs energy from the ultrasonic field. The motivation of this study lies in the possibility of using gas microbubbles as an aid to therapeutic focused ultrasound treatments.     

QSAR with experimental and predictive distributions: an information theoretic approach for assessing model quality

We propose that quantitative structure–activity relationship (QSAR) predictions should be explicitly represented as predictive (probability) distributions. If both predictions and experimental measurements are treated as probability distributions, the quality of a set of predictive distributions output by a model can be assessed with Kullback–Leibler (KL) divergence: a widely used information theoretic measure of the distance between two probability distributions. We have assessed a range of different machine learning algorithms and error estimation methods for producing predictive distributions with an analysis against three of AstraZeneca’s global DMPK datasets. Using the KL-divergence framework, we have identified a few combinations of algorithms that produce accurate and valid compound-specific predictive distributions. These methods use reliability indices to assign predictive distributions to the predictions output by QSAR models so that reliable predictions have tight distributions and vice versa. Finally we show how valid predictive distributions can be used to estimate the probability that a test compound has properties that hit single- or multi- objective target profiles.     

The effect of wave reflection and refraction at soft tissue interfaces during ultrasound hyperthermia treatments.

An improved numerical model for calculating the ultrasonic power deposition in layered medium was developed and experimentally tested. The new model takes into account the ultrasound wave reflection and refraction at the tissue interfaces thereby providing improved accuracy in ultrasound hyperthermia treatment planning. The model was compared with a simplified model to evaluate when the tissue interfaces could be ignored in the hyperthermia treatment planning and evaluation. The effect of variations in water and tissue temperatures, the fat layer thicknesses, and the beam entrance angle were also investigated to establish guidelines for treatment execution. It was found that in most cases the effects of the soft tissue interfaces can be ignored. However, in some instances the acoustic focus may be shifted several millimeters off axis in layered medium. This is important when sharply focused transducers are used for ultrasound surgery or under the condition of pulsed, high-temperature hyperthermia treatments.     

Progress and problems in the application of focused ultrasound for blood-brain barrier disruption

Advances in neuroscience have resulted in the development of new diagnostic and therapeutic agents for potential use in the central nervous system (CNS). However, the ability to deliver the majority of these agents to the brain is limited by the blood-brain barrier (BBB), a specialized structure of the blood vessel wall that hampers transport and diffusion from the blood to the brain. Many CNS disorders could be treated with drugs, enzymes, genes, or large-molecule biotechnological products such as recombinant proteins, if they could cross the BBB. This article reviews the problems of the BBB presence in treating the vast majority of CNS diseases and the efforts to circumvent the BBB through the design of new drugs and the development of more sophisticated delivery methods. Recent advances in the development of noninvasive, targeted drug delivery by MRI-guided ultrasound-induced BBB disruption are also summarized.     

Reproducibility of serum protein profiling by systematic assessment using solid-phase extraction and matrix-assisted laser desorption/ionization mass spectrometry

Protein profiling of human serum by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) is potentially a new diagnostic tool for early detection of human diseases, including cancer. Sample preparation is a key issue in MALDI MS and the analysis of complex samples such as serum requires optimized, reproducible methods for handling and deposition of protein samples. Data acquisition in MALDI MS is also a critical issue, since heterogeneity of sample deposits leads to attenuation of ion signals in MALDI MS. In order to improve the robustness and reproducibility of MALDI MS for serum protein profiling we investigated a range of sample preparation techniques and developed a statistical method based on repeated analyses for evaluation of protein-profiling performance of MALDI MS. Two different solid-phase extraction (SPE) methods were investigated, namely custom-made microcolumns and commercially available magnetic beads. Using these two methods, nineteen different sample preparation methods for serum profiling by MALDI MS were systematically tested with regard to matrix selection, stationary phase, selectivity, and reproducibility. Microcolumns were tested with regard to chromatographic properties; reversed phase (C8, C18, SDB-XC), ion-exchange (anion, weak cation, mixed-phase (SDB-RPS)) and magnetic beads were tested with regard to chromatographic properties; reversed phase (C8) or affinity chromatography (Cu-IMAC). The reproducibility of each sample preparation method was determined by enumeration and analysis of protein signals that were detected in at least six out of nine spectra obtained by three triplicate analyses of one serum sample.A candidate for best overall performance as evaluated by the number of peaks generated and the reproducibility of mass spectra was found among the tested methods. Up to 418 reproducible peaks were detected in one cancer serum sample. These protein peaks can be part of a possible diagnostic profile, suggesting that this sample preparation method and data acquisition approach is suitable for large-scale analysis of serum samples for protein profiling.     

Picosecond passively mode-locked GaSb-based semiconductor disk laser operating at 2 μm

We report on a passively mode-locked optically pumped GaSb-based semiconductor disk laser producing stable picosecond optical pulses at a 1.95 μm wavelength. The gain mirror was comprised of a 15 quantum well InGaSb/GaSb structure. A fast semiconductor saturable absorber mirror with three InGaSb/GaSb quantum wells was used to attain self-starting mode-locked operation at a fundamental repetition rate of 881.2 MHz. The laser produced pulses with 30 pJ energy and a duration of 1.1 ps within a factor of 2 of the Fourier limit.     

A regular decomposition of the edge-product space of phylogenetic trees

We investigate the topology and combinatorics of a topological space called the edge-product space that is generated by the set of edge-weighted finite labelled trees. This space arises by multiplying the weights of edges on paths in trees, and is closely connected to tree-indexed Markov processes in molecular evolutionary biology. In particular, by considering combinatorial properties of the Tuffley poset of labelled forests, we show that the edge-product space has a regular cell decomposition with face poset equal to the Tuffley poset.     

Preventive Support for Kindergarteners Most At-Risk for Mathematics Difficulties: Computer-Assisted Intervention

Weaknesses in early number skills have been found to be a risk factor for later difficulties in mathematical performance. Nevertheless, only a few intervention studies with young children have been published. In this study, the responsiveness to early support in kindergarteners with most severe difficulties was examined with two different computer programs. Two intervention groups were matched by age, visuo-spatial, and phonological working memory, as well as early number skills. After a short and intensive computerized intervention, the results indicated significant intervention effects for verbal counting Wilcoxon ES (r) = 0.46, and dot counting fluency, r = 0.52, when practiced with GraphoGame Math, as well as for basic arithmetic, r = 0.63, when practiced with Number Race. The findings suggest that a targeted computerized practice can produce specific training effects in kindergarteners most at-risk for mathematics difficulties. The results are discussed with regard to practical implications for educational game development.