Previous studies from our group reported that the

Previous studies from our group reported that the parameters cited in this study are not the only parameters that may be applied without causing damage (Tung et al. 2010). Methods of examining alternate variables in the previous studies were based on histologic processing (Baseri et al. 2010). However, the results from our previous studies provided a reference for the upper limit of the pressure variable without inducing damage (Tung et al. 2010). Most pressures at and below 0.45 MPa, but above 0.30 MPa, using Definity microbubbles have been found to open the BBB without causing cerebral damage (Choi et al. 2010a). However, cerebral damage can occur if ultrasound parameters are not carefully chosen. In this study, we deliberately chose 1.5 MPa for the positive control group to illustrate behavior changes in these mice. A significant decrease in motor function and coordination is apparent at a peak negative pressure of 1.5 MPa (Fig. 4a, c). Nonetheless, all mice were able to recover from the injury; in addition, it was found through histologic analysis that the cerebral morphology 4 wk after application of ultrasound was close to that of group B1 (Fig. 8), with a survival period of 4 wk and a peak negative pressure within the safety (0.45 MPa) window, suggesting damage was reversible (Tung et al. 2010). Histological analysis revealed no differences in damage between groups over durations ranging from 1 to 6 months of survival with repeated FUS application, including the n = 5 group P that was sacrificed 1 month after sonication (Fig. 9). The group P mice (n = 3), which were sacrificed 24 h after sonication, had extravasated serine protease inhibitors as well as dark neurons (Fig. 8).
Other researchers have reported the tolerability and feasibility of BBB opening with FUS in other animals. The procedure has been assessed in rats (Kim et al. 2014) and rabbits (Hynynen et al. 2005; McDannold et al. 2005), and tolerability has been further assessed behaviorally in non-human primates (Downs et al. 2014; McDannold et al. 2012).

Conclusions

Acknowledgments
This research was supported in part by National Institutes of Health (NIH) Grants RO1 EB009041 and RO1 AG038961 and the Kinetics Foundation.

Introduction
Ultrasound molecular imaging features high sensitivity, availability, rapid execution of imaging protocols and relatively low cost (Kaufmann and Lindner 2007; van Rooij et al. 2015), and its potential for imaging biological processes at the molecular level has been illustrated. The key element of this technique compared with regular diagnostic ultrasound imaging is the use of ultrasound contrast agents (UCAs) decorated with binding ligands such as antibodies and small peptides. These functionalized UCAs, so-called targeted UCAs (tUCAs) or targeted microbubbles, can bind to biomarkers involved in various disease processes. As UCAs are blood pool agents (Greis 2009), tUCAs can only bind to intravascular biomarkers on intravenous administration. Combined with dedicated ultrasound imaging sequences and the latest transducer technology, ultrasound molecular imaging allows quantitative assessment of molecular target expression with high sensitivity. The aforementioned features of this technique have opened new diagnostic applications, including the detection of atherosclerosis (Kaufmann 2009; Khanicheh et al. 2013a, 2013b; Liu et al. 2013; Shim et al. 2015), thrombosis (Alonso et al. 2007), neovasculature (Deshpande et al. 2011; Leong-Poi et al. 2003; Shelton et al. 2016; Stieger et al. 2008; Streeter et al. 2013), lymph nodes (Hauff et al. 2004) and inflammation (Bettinger et al. 2012; Davidson et al. 2014; Lindner 2010; ten Kate et al. 2010). It also provides helpful insights into the genesis, progress and prevention of diseases (Dayton and Ferrara 2002; Khanicheh et al. 2013a; Klibanov 2006; Lanza et al. 1996; Lindner 2004; Liu et al. 2013; Palmowski et al. 2008; Shim et al. 2015; Streeter et al. 2013; van Rooij et al. 2015).

br Acknowledgments br This research was supported by the

Acknowledgments

This research was supported by the Canadian Institute of Health Research (MOP 136842), the National Institutes of Health (1R01EB018975), the Burroughs Wellcome Career Award at the Scientific Interface and FUJIFILM VisualSonics.

Introduction
The drug product consists of an aqueous dispersion of lipid-stabilized perfluorobutane (PFB)-filled gas microbubbles (MB) with a median volume diameter of approximately 3 μm (Sontum et al. 1999) (Fig. 1). The microbubbles are stabilized with a monolayer of phospholipids obtained from hydrogenated egg phosphatidylserine, with palmitoyl-stearoyl-phosphatidylserine as the main constituent (Hvattum et al. 2006).
The currently approved clinical dose for liver and breast imaging is 0.12 μL MB/kg body weight (b.w.). After intra-venous injection, the microbubbles are restricted to the intra-vascular compartment, but have no molecular targets within the blood vessels. In the liver sinusoids, however, Sonazoid is taken up by Kupffer gsk-3 and eventually degraded. In the case of ultrasound imaging of the liver, contrast enhancement is initially based on the presence of intact MB in the luminal compartment of blood vessels (vascular imaging) (Forsberg et al. 2000; Moriyasu and Iijima 2002) and later in the Kupffer cells of the liver (Kupffer cell imaging) (Forsberg 2000, 2002; Kindberg 2003; Yanagisawa 2007). The phospholipids are metabolized in the liver, and the metabolites are most probably completely oxidized or incorporated into the endogenous lipid pool. No metabolic system for degradation or conjugation of PFB has been reported, and the PFB gas is expected to be released unchanged from the liver back into the circulation. PFB is very hydrophobic and has very low solubility in water, but because of the small doses administered, the PFB could theoretically be completely dissolved in the aqueous phase of the liver before it is released into the circulation. Alternatively, it may be released as naked PFB microbubbles (gas bubbles without a lipid covering) or encapsulated in lipoproteins together with other hydrophobic compounds such as triacylglycerols. PFB that has been released into circulation will then be expired via the lungs and, to some extent, taken up in fat tissues.
A gas chromatography tandem to mass spectrometry (GC-MS) analytical method for determination of PFB was developed and has been used in a previous pharmacokinetic (PK) study of Sonazoid performed by GE Healthcare. That study was a phase 1 study in Caucasian healthy volunteers (HVs) and patients with abnormal pulmonary diffusion capacity who received 0.6 μL MB/kg b.w. Sonazoid by bolus injection or infusion (Landmark et al. 2008). After bolus administration of 0.6 μL MB/kg b.w. Sonazoid to Caucasian HVs, blood concentrations of PFB declined rapidly and biphasically. The Cmax value of PFB in blood after bolus administration of 0.6 μL MB/kg b.w. Sonazoid in Caucasian HVs was 28.9 ± 7.2 ng/g, and the area under the curve (AUC) value was 172.7 ± 28.0 ng × min/g (mean ± standard deviation [SD]). The time of the maximum observed concentration (tmax) generally occurred between 0.5 and 2 min after injection. The mean ± SD terminal blood elimination half-life in Caucasian HVs was 34.5 ± 5.7 min. After bolus administration, clearance and volume of distribution appeared to be independent of study population and gender. Concentrations of PFB in exhaled air declined biphasically after bolus administration of Sonazoid. The mean ± SD elimination half-life in HVs was 31.7 ± 4.3 min. The Cmax value of PFB in exhaled air in Caucasian HVs was 3.5 ± 1.6 ng/g (mean ± SD), and the AUC value was 44.0 ± 11.4 ng × min/mL (mean ± SD).
The objective of the present study was to describe the PK properties and safety of Sonazoid in Chinese HVs after a bolus injection of Sonazoid at two dose levels: the clinical dose of 0.12 μL MB/kg b.w. and a high dose of 0.60 μL MB/kg b.w. The study results are discussed in comparison to the data obtained for Caucasian HVs (Landmark et al. 2008), with the focus on possible ethnicity-related variation of Sonazoid PK properties. As no metabolic system for degradation of PFB is known and no metabolites of PFB have been observed during the non-clinical and clinical testing of this agent, it was expected that the PKs of PFB in blood and exhaled air would not differ between different populations. The results obtained in the present study help to illustrate the extent of potential ethnic variability in the PKs of Sonazoid and other gas-filled microbubble-based ultrasound contrast agents.

The largest strains are experienced

The largest strains are experienced by particles starting at the bubble wall when the bubble reaches its maximum and minimum radii; exact expressions for the maximum radial compressive, polar tensile, radial tensile and polar compressive strains are summarized in Table 1. First, when the bubble achieves its maximum radius, radial strain at the bubble wall is compressive and polar strain at the bubble wall is tensile, corresponding to the maximum radial compressive and polar tensile stresses. In contrast, the largest radial tensile and polar compressive strains occur when the bubble collapses to its minimum radius, Rmin < R0. At this instant, the tissue is fully released from the compressive radial strain that occurred during bubble growth, and the strain changes direction. These strains occur over an exceedingly short time and attenuate much more rapidly into surrounding tissue than the strains generated at maximum bubble radius. As seen in Figure 7, Lagrangian particles starting as close as 1 μm from the bubble nucleus experience negligible radial tensile strain at bubble collapse. The highest strain rates occur at instants of initial bubble growth and late collapse, with maximum values ranging from 105 s−1 for a Lagrangian particle starting at a distance of 200 μm from the bubble wall to 108 s−1 at a distance of 1 μm from the bubble wall. The highest strain rates coincide with the peaks in radial tensile stress and strain that occur at the bubble wall at Rmin.
Results: Parametric Study
The effects of tissue (viscosity, shear modulus) and waveform (negative pressure, frequency) properties, as well as initial bubble radius, on maximum radial stresses and strains experienced by a Lagrangian particle (e.g., a cell) are evaluated. The Lagrangian viewpoint is of practical relevance because it T-5224 manufacturer enables one to determine the loads experienced by a cell, initially at some distance from the nucleation site, over the course of bubble growth and collapse. In all of the following maximum stress (Figs. 9, 12, 15, 18, 21) and strain (Figs. 10, 13, 16, 19, 22) figures, the horizontal axis gives the starting point of a particle within 50 μm from the bubble nucleus, with 500 sample points. The vertical axis has the highest magnitude of total stress (combined elastic and viscous) or strain experienced by a cell that starts at a given distance from the nucleus. Because of their typically distinct origins, maximum compressive and tensile stresses are considered separately. As a reference, a water case in which viscosity and shear modulus are fixed at μ = 1 mPa·s and G = 0 Pa is used when tissue material properties are varied. Results are provided for radial stresses and strains; tissue is also experiencing polar stresses and strains, of opposite sign and half the magnitude.

Discussion
Experimental studies suggest that tissue properties play a key role in determining tissue susceptibility to cavitation generation and histotripsy-induced tissue damage (Vlaisavljevich et al. 2013). Our results highlight the importance of elasticity, viscosity, peak negative pressure and waveform frequency to hypothesized mechanical tissue damage mechanisms. An improved understanding of cavitation damage mechanisms will help predict damage susceptibility of different tissues, as well as differential damage responses within a focal region under different acoustic parameters. This knowledge can ultimately be used to guide safety considerations and enable treatment planning.
Figure 25 and Table 2 illustrate the relationships between the maxima in total stress, strain and strain rate by highlighting three key points during a single cycle of bubble growth and collapse that correspond to relative or absolute maxima in these field quantities. First, a tensile histotripsy pulse drives the onset of explosive bubble growth when R = R0. At this time, viscous effects predominate and both the strain rate and compressive stress achieve relative maxima. At distances greater than xEV (the elastic-to-viscous transition point), this maximum in compressive viscous stress at the onset of bubble growth will also contribute the absolute maximum total compressive stress during the life span of the bubble. Next, bubble growth proceeds rapidly until viscous resistance and tissue stiffness limit growth to a maximum radius, R = Rmax. Here, tissue elasticity has the dominant influence on bubble dynamics. Both the compressive stress and compressive strain are maximized, whereas the strain rate and viscous stress are negligible. At distances less than xEV, this maximum in compressive elastic stress contributes the absolute maximum total compressive stress over the life span of the bubble. Finally, the bubble undergoes a violent collapse to a minimum radius Rmin < R0. At minimum radius, viscous effects again dominate, and tensile stress, tensile strain, and strain rate are all maximized. Tensile stress is purely viscous in origin and contributes the absolute maximum total stress when viscosity is sufficiently large.

Recently the synthetic approaches of Pd Ni bimetallic NPs

Recently, the synthetic approaches of Pd−Ni bimetallic NPs have been developed by many research groups, such as wet chemical methods,‌ electrodeposition and template-directed fabrication [50–52]. Also, the Pd-based bimetallic nanostructures with inexpensive transition metals such as Fe, Co and Ni as the new catalysts show good selectivity, stability, and activity in various organic reactions [53–55]. In this study, we have reported the ultrasonic assisted-one-pot method for the synthesis of core–shell Pd−Ni/Fe3O4 nanoalloys, which show highly enhanced activity toward the Suzuki-Miyaura coupling reaction. There are some reports about using Pd-Ni bimetallic alloys in Suzuki-Miyaura CC coupling reaction, but it is imperative to develop facile synthetic strategies for Pd−Ni alloy NPs with excellent catalytic performance. Our synthesized core–shell alloy catalyst is less expensive, involving inexpensive and abundantly available non-noble metals, than Pd-monometallic complexes for Suzuki-Miyaura reaction. Also, separating of Fe3O4-supported metal catalysts from the reaction medium by an external magnet is one of the main advantages of these kinds of catalysts.

Material and methods
Mercaptosuccinic acid, ferric chloride hexahydrate (FeCl3·6H2O), ferrous chloride tetrahydrate (FeCl2·4H2O), ammonia (25 wt‌‌%), nickel nitrate (Ni)NO3)2) and palladium chloride (PdCl2) were purchased from Merck company. Sodium tetrahydroborate (NaBH4) was purchased from Panreac. All chemicals were used as received. X-ray diffraction (XRD) patterns of the as-prepared catalysts were recorded using a Bruker AXS (D8, Advance) instrument equipped with Cu-Kα radiation. Transmission Cyclo cost microscopy (TEM) images of the catalysts were recorded using a Philips CM-30 TEM microscope operated at 100kV. Fourier-transform infrared spectroscopy spectra were obtained with a FT-IR8600 spectrometer (JASCO Co., Japan). Inductively coupled plasma (ICP) was performed on Agilent 7500ce quadrupole ICP-AES. The UV–Vis spectra were recorded using a Lambda 25 spectrophotometer (PerkinElmer). 1H NMR spectra were obtained with a Bruker 400MHz Ultra-shield spectrometer using CDCl3 as the solvent (See Supporting Information file). Also, 13C NMR spectra were obtained using CDCl3 as the solvent (See the Supporting Information file). The turnover number (TON (= mol of product/mol of catalyst)) and turnover frequency (TOF (= TON/time (h))) were calculated on the basis of the amount of biaryl product formed.

Results and discussion

Conclusions
In this study, for the first time, a facile route for the synthesis of [email protected] core–shell nanostructures has been demonstrated by ultrasonic assistance. Sonochemical reduction of metal salts has some advantages than other reduction methods that used for metallic nanostructures formation: (i) fast rate of the reaction, (ii) small particle size, (iii) using no reducing agent. The [email protected] core–shell nanostructures exhibit excellent catalytic performance for the suzuki reaction and 4-NP reduction. These catalysts were magnetically separated from the reaction mixture and exhibited high catalytic activity for at least six cycles. Furthermore, non-noble metal in the presence of Pd affect the electronic structure of the Pd by the electron transfer effect that is the result of the differences in the electronegativity of the two metals. In other words, ‌using non-noble metal near the Pd can disturb the electronic structure of the Pd and change the highest occupied and lowest unoccupied molecular orbitals of these metals due to the electron transfer effect. One of our main aims to produce [email protected] core–shell is the development of a class of highly active nanoalloy catalysts with the following advantages: (i) the use of Pd for coupling reactions can be minimized. This will lead to reduce the catalyst cost due to applying a second inexpensive non-noble metal, (ii) using the [email protected] core–shell as catalyst with a Fe3O4 core and Pd-Ni shell leads to a less Pd consumption and all the active Pd metal atoms are on the surface of the catalyst. (iii) This strategy is simple, economical and promising for industrial applications.

br Materials and measurement methods The measurements were made

Materials and measurement methods
The measurements were made in three different liquid media. The first of them is tap water that was left to settle for at least 24h before the measurements, with the density of 960kg/m3, sound speed velocity of 1498m/s, characteristic acoustic impedance of 1.49·106kg/(m2·s) and viscosity of 1·10−3Pa·s. The second medium was fresh homogenized milk with the density of 1035kg/m3, sound speed velocity of 1548m/s, characteristic acoustic impedance of 1.60·106kg/(m2·s), and the viscosity of 2·10−3Pa·s. The third selected medium was clear apple juice with the density of 1046kg/m3, sound speed velocity of 1500m/s, characteristic acoustic impedance of 1.57·106kg/(m2·s), and the viscosity of 1·10−3Pa·s. All the parameters are given for room temperature. These particular samples were chosen because they are among the most commonly used beverages in the average population. Both the transducer and these specific food samples were characterized to optimize the high-power ultrasonic processing applied to such samples [21–23]. Numerical values of energy, pressure, heat, temperature, and power per unit molecule to be mechanically “cut” are of the essence, if functional products such as bioactive met inhibitor or short length chains of carbohydrate for i.e. waste treatment in food industry are to be obtained. Acoustic processing in terms of amplitude, processing time, temperature needs to be optimized, if bioactive compounds are to remain undisturbed and chemically unchanged, and their activity preserved [24,25].

Results and discussion
This section shows the results of full electromechanical characterization of the sonoreactor made at several excitation levels. Using the equivalent electrical RLC circuit approach, the electroacoustical efficiency factor ηeam was found. The measurements of radiated acoustic power in the small sonoreactor assuming diffuse pressure field yielded the factor ηear. The calorimetric measurements of the dissipated acoustic power yielded the factor ηeac.

Conclusion
The electromechanical characterization made by measuring the input electrical admittance in linear driving conditions around resonance is a very good way of checking the linear performance of the device. The measured efficiency factor with electromechanical characterization at resonance (ηeam=88.7%) and out of resonance (ηeam=85.2%) can be compared with the efficiency factor obtained from irradiated acoustic power measurements assuming diffuse sound field (ηea=84.9%) at low excitation levels when there are no nonlinear effects in loading media. At higher excitation levels, the spatial variation of the pressure magnitude is even lower in the complex sound field influenced by nonlinear effects. In this case, the irradiated acoustic power is much lower than the dissipated acoustic power measured by using the calorimetric method.
The input electrical admittance and other measured parameters such as side displacement and pressure are significantly decreased at resonance when the transducer is driven with a high-level constant-voltage frequency sweeping signal, with nonlinear effects such as bubble oscillation and acoustic streaming appearing in loading media. The resonance peak (electrical admittance, displacement, pressure) becomes wider due to additional losses in the media that exhibit nonlinear processes. These losses cannot be explained only with a simplified radiation impedance consideration, i.e. the decrease of the specific acoustic impedance (ρeff·ceff) of the loading medium in front of the sonotrode tip, caused by water-bubble liquid mixture forming in front of the tip. The decrease of the pressure maximum around the excitation mode at some position in the vessel can be explained with the decrease of the specific medium impedance between the sonotrode and the measurement point and, consequently, lower pressure in the loading media due to higher absorption. Acoustic streaming in front of the tip reduces the imaginary part of the characteristic acoustic impedance of the effective medium, which is visible from the increase of imaginary part of electrical admittance measured at higher excitation levels close to resonance.

mao inhibitors In addition to tissue treatment HIFU has also

In addition to tissue treatment, HIFU has also been utilized to locally heat polymer materials thereby triggering drug release or shape memory [8,9]. In general, mao inhibitors of ultrasound due to internal friction and relaxation results in a heating effect in visco-elastic polymer materials. The HIFU-induced heating effect in different polymer materials (PE-LLD, PE-LD, PE-HD, PA-6, PP, PS, PC and PMMA) was investigated by Liu et al. [10]. They placed a 1.1MHz focusing piezoceramic ultrasonic transducer in a water-filled tank and irradiated solid polymer samples located at the water surface. The HIFU power was 8W at maximum to avoid cavitation. Non-invasive temperature measurement was done by infrared thermal imaging at the back surface of the samples. A correlation between the HIFU-induced thermal effect and the type of polymer materials was found, which was explained by different absorption coefficients of the different polymer materials due to differences in inner friction behaviors of macromolecular chains. The maximum equilibrium temperature was found for PMMA with 180°C after 25s of irradiation with 4W HIFU power. PE-LD was heated up to 80°C after 20s at 4W. For higher HIFU power a material-dependent threshold of 6–8W for sample damage was found. Furthermore, the authors described different initial temperature rises for the different polymer materials, the highest one for PP. Both the equilibrium temperature and the initial temperature rise were found to be dependent on the sample thickness in case of PE-LD. Increasing sample thickness results in increasing equilibrium temperature and decreasing initial temperature rises. They explained the increasing equilibrium temperature with the enlarged “focused volume, which makes the sample absorb more ultrasound energy” [10]. Similar results were obtained by Li et al. for shape memory polymer P(MMA-BA) [9]. Investigations with higher HIFU power on the same shape memory polymer material were done by Li et al. [8]. They reported a polymer heating of 140°C in the samples after 10min of irradiation at 50W HIFU power, which was measured by embedded thermocouples [8]. Further reports on HIFU-induced thermal heating have been published by Hallez et al. [11] and Huamao et al. [12]. However, in all known investigations water has been used for sound transmission and the HIFU power was limited to 50W to avoid cavitation. As a result, the temperature rise of the samples was limited and the irradiation times for reaching the equilibrium temperature were several seconds.
Rapid local heating of solid polymers is of broad interest for several areas of application in the field of polymer processing, such as forming or welding. However, the implementation of HIFU in these applications requires an understanding of the heating effect at high HIFU power. To circumvent cavitation, it is necessary to substitute water as the sound-transmitting medium. A number of medical devices possess solid coupling cones build from e.g. aluminum for sound transmission [13]. In this study, this ultrasonic applicator design is adapted by using an ultrasonic applicator with solid aluminum sound conductor. To the best of our knowledge the HIFU-induced heating effect in solid polymer materials has not yet been investigated using a solid sound conductor.

Experimental section

Results and discussion

Conclusion
The HIFU-induced heating of solid PE-LD using a solid sound conductor for sound transmission from a piezoceramic transducer to the samples was investigated. Our investigations showed that high ultrasonic energy can be mao inhibitors coupled into solid polymer samples for strong heat generation using a HIFU ultrasonic applicator with solid sound conductor. For inducing the heating effect an acoustic coupling of the sound conductor to the sample is required, which can be performed by applying a jacking force. We have found that the heating profile in the xy-plane is quite different to profiles obtained from coupling with water published by other researchers [9,10]. The irradiated volume was characterized by hot spots. The temperature in the hot spots reached the melting temperature and even the evaporation temperature within less than 1s irradiation time. An indicator for temperature rise was found in the form of a discontinuity in the output power curve. These findings are relevant for processes in which solid polymers need to be heated quickly and locally such as in welding or forming. Future work will investigate the heating effect in other thermoplastic polymer materials, different sample thickness and the influence of the material and thickness of the counterholder that was limited to sapphire glass in this study.

mao inhibitors In addition to tissue treatment HIFU has also

In addition to tissue treatment, HIFU has also been utilized to locally heat polymer materials thereby triggering drug release or shape memory [8,9]. In general, mao inhibitors of ultrasound due to internal friction and relaxation results in a heating effect in visco-elastic polymer materials. The HIFU-induced heating effect in different polymer materials (PE-LLD, PE-LD, PE-HD, PA-6, PP, PS, PC and PMMA) was investigated by Liu et al. [10]. They placed a 1.1MHz focusing piezoceramic ultrasonic transducer in a water-filled tank and irradiated solid polymer samples located at the water surface. The HIFU power was 8W at maximum to avoid cavitation. Non-invasive temperature measurement was done by infrared thermal imaging at the back surface of the samples. A correlation between the HIFU-induced thermal effect and the type of polymer materials was found, which was explained by different absorption coefficients of the different polymer materials due to differences in inner friction behaviors of macromolecular chains. The maximum equilibrium temperature was found for PMMA with 180°C after 25s of irradiation with 4W HIFU power. PE-LD was heated up to 80°C after 20s at 4W. For higher HIFU power a material-dependent threshold of 6–8W for sample damage was found. Furthermore, the authors described different initial temperature rises for the different polymer materials, the highest one for PP. Both the equilibrium temperature and the initial temperature rise were found to be dependent on the sample thickness in case of PE-LD. Increasing sample thickness results in increasing equilibrium temperature and decreasing initial temperature rises. They explained the increasing equilibrium temperature with the enlarged “focused volume, which makes the sample absorb more ultrasound energy” [10]. Similar results were obtained by Li et al. for shape memory polymer P(MMA-BA) [9]. Investigations with higher HIFU power on the same shape memory polymer material were done by Li et al. [8]. They reported a polymer heating of 140°C in the samples after 10min of irradiation at 50W HIFU power, which was measured by embedded thermocouples [8]. Further reports on HIFU-induced thermal heating have been published by Hallez et al. [11] and Huamao et al. [12]. However, in all known investigations water has been used for sound transmission and the HIFU power was limited to 50W to avoid cavitation. As a result, the temperature rise of the samples was limited and the irradiation times for reaching the equilibrium temperature were several seconds.
Rapid local heating of solid polymers is of broad interest for several areas of application in the field of polymer processing, such as forming or welding. However, the implementation of HIFU in these applications requires an understanding of the heating effect at high HIFU power. To circumvent cavitation, it is necessary to substitute water as the sound-transmitting medium. A number of medical devices possess solid coupling cones build from e.g. aluminum for sound transmission [13]. In this study, this ultrasonic applicator design is adapted by using an ultrasonic applicator with solid aluminum sound conductor. To the best of our knowledge the HIFU-induced heating effect in solid polymer materials has not yet been investigated using a solid sound conductor.

Experimental section

Results and discussion

Conclusion
The HIFU-induced heating of solid PE-LD using a solid sound conductor for sound transmission from a piezoceramic transducer to the samples was investigated. Our investigations showed that high ultrasonic energy can be mao inhibitors coupled into solid polymer samples for strong heat generation using a HIFU ultrasonic applicator with solid sound conductor. For inducing the heating effect an acoustic coupling of the sound conductor to the sample is required, which can be performed by applying a jacking force. We have found that the heating profile in the xy-plane is quite different to profiles obtained from coupling with water published by other researchers [9,10]. The irradiated volume was characterized by hot spots. The temperature in the hot spots reached the melting temperature and even the evaporation temperature within less than 1s irradiation time. An indicator for temperature rise was found in the form of a discontinuity in the output power curve. These findings are relevant for processes in which solid polymers need to be heated quickly and locally such as in welding or forming. Future work will investigate the heating effect in other thermoplastic polymer materials, different sample thickness and the influence of the material and thickness of the counterholder that was limited to sapphire glass in this study.

br Conclusions After analyzing the acoustic

Conclusions
After analyzing the acoustic data, it can be stated that the acoustic technique based on signal processing of sound produced by GAC flooded with water is a useful tool for determining porous characteristics of granular activated carbons. Certainly as a fast and correct predicting method of the exhaustion level of GACs used in the rum production, it is already successful. It is proved that the sound surface SS of the GAC can be satisfactory correlated with SBET, VDR and using water as flooding liquid and 1000Hz as the main frequency component.

Acknowledgements
The authors would like to thank VLIR-UOS project between Belgium and Cuba for providing funding and granting the support of the current and future studies.

Introduction
Coronary artery disease (CAD), also known as atherosclerosis, is the most common type of cardiovascular disease and the leading cause of death globally [1]. Atherosclerosis is a slow-progressing and systemic disease characterized by the formation of plaques through the deposition of calcium, fibrin, cholesterol, fat, and other substances in the intima of large and medium arteries, including the aorta, coronary artery, and peripheral ldk378 [2–4]. An unstable atherosclerotic plaque may rupture, leading to the formation of a thrombus that can obstruct coronary artery branches and cause an acute myocardial infarction [5]. Several clinical imaging modalities are frequently used for diagnosing the atherosclerosis, such as coronary computed tomography [6], coronary angiography [7,8], myocardial perfusion scanning [9], magnetic resonance imaging [10], and intravascular ultrasound (IVUS) imaging [11,12]. However, most of these methods provide only image-based morphological features, and this information is insufficient for predicting plaque rupture [13]. Several studies have revealed that a lipid-rich plaque may rupture and break away from the vessel wall when it cannot withstand the stress imposed by the pulsatile pressure of the blood [14]. This plaque vulnerability is influenced by the mechanical properties of both the vessel wall and the plaque itself. Therefore, the ability to quantitatively estimate the mechanical properties of the lipid-rich plaque and arterial vessel wall would be important in clinical diagnosis since it would allow the physician to determine the degree of arteriosclerosis and the risk of plaque rupture [15,16].
During the past two decades, ultrasound elastography has been used widely for assessing the mechanical properties of soft tissues [17]. It can be used to determine the stiffness distributions within a tissue by applying an external force that slightly deforms the tissue. This technique has been implemented in clinical ultrasound systems, such as Siemens Acuson Antares and Samsung-Medison SonoAce X8. Since the resolution of traditional systems is insufficient, noninvasive elastography has limited practicality in clinical applications related to CAD. It is considered that the resolution of elastography should be as close as around 100μm which is the resolution of commercial IVUS image used for intravascular coronary detection [18]. In order to overcome this problem, intravascular elastography was proposed to detect the strain distributions of a plaque and epicardial vessels by applying an external force using a compliant intravascular balloon [19]. However, since such a balloon applies a nonuniform force, the strain estimations of the plaque and vessel may be inaccurate. A modified method, measuring the strain distributions of the plaque and vessel wall strained at different levels of intraluminal pressure, was therefore proposed. First, De Korte et al. reported the concept and used vessel phantoms with the morphology of an artery with an eccentric soft (30kPa) or hard (120kPa) plaque to validate the method [20]. The strain is determined in a significant part of the vessel wall and plotted as a color-coded ring (palpogram) at the lumen vessel–wall boundary [21]. The first real-time clinical intravascular elasticity imaging system operating at frequency of 20MHz was proposed [22]. An in vitro experiment was performed using excised human coronary and femoral arteries at intraluminal pressures of 80 and 100mmHg [23]. Furthermore, 20-MHz IVUS elastography data were collected from 12 patients undergoing percutaneous transluminal coronary angioplasty in a clinical study [24], in which a systemic pressure difference was used to strain the vessel. The experimental results showed that calcified and noncalcified plaques exhibited strains of 0.20% and 0.51%, respectively. These studies have demonstrated the feasibility of IVUS elastography in vivo. However, a major problem of intravascular elastography is the acquisition of data in a pulsating artery located in a contracting heart. The catheter will move in the artery and this will result in a mismatch of the data recorded at the low and high pressure (approximately 100–150mmHg) [24]. To avoid detection at different tissues, the acquisition frames can be collected near end-diastole, which has a pressure difference of 4–5mmHg determined using elastograms. A smaller pressure difference immediately results in lower strain values. The elastic value is directly associated with the stress ratio (i.e., pressure) and strain. Therefore, a slightly erroneous pressure measurement would cause considerable errors in elastic property estimation.

A laser stimulated source in general combines light pressure thermal

A laser-stimulated source, in general, combines light pressure, thermal expansion due to light absorption, electrostriction, and material ablation as means of producing ultrasonic waves. Each of these mechanisms may be experimentally fairly well isolated with appropriate selection of elastic materials and their surface treatments, laser energies and wavelengths [1,2].
Drawing additional inspiration from the analogies with seismology [45–50], we derive a formulation that combines the light-pressure and light-absorption effects in a laser-illuminated volume on a solid surface and treats it as common ultrasonic source. We show how such a source, through a series of transfer functions, is responsible for material displacement in elastic material. The presented formulation [51–53] utilizes Huygens’ superposition principle that is statistically stremlined by means of geometric probability theory [54] for constructing the required volume-to-volume transfer functions out of weighted and superimposed point-to-point Greens’ functions. The desired waveforms are then obtained from them by temporal convolutions with the source inputs. In our case, the Green’s functions were originally derived by Hsu [31]. This general formulation is as a simple method for obtaining sufficiently detailed volume-to-volume transfer functions and subsequent displacement waveforms while accounting for arbitrary source and observation distributions [51–53].
The results are visualized as three-dimensional line plots and shaded surface plots as well as animated videos available as supplementary material on-line. Particular attention is given to individual wave arrivals and their effects on the waveforms. Selected simulated waveforms are compared to the independent models from the literature [2,20,40].
In addition to being a theoretical study of ultrasound generation and propagation, the purpose of such simulated waveforms is to introduce well formulated underlying physical concepts and mechanisms to the interpretation and evaluation of the corresponding experimental data. In a particular experimental setup, the measured SBI-0206965 signal should be compared to the simulated waveforms modeled for the same geometric arrangement, the same materials, and the same stimulating laser pulse, while accounting for the sensor transfer function as well. A good match between them should indicate that the correct physical assumptions have been made. Such a process was used and is described in detail in some of our previous work [51,52].
Due to conceptual and theoretical nature of this paper, no measurements are presented. Some may be found throughout the literature [1,2,6,12–16,18,20,24,26,30,32–36,39,40,42,44,51,52].

Formulation of laser-induced ultrasound
A consistent mathematical description of ultrasound generation mechanisms in laser ultrasonics is achieved by implementation of analogous formulations used for mechanical excitations of matter that are rooted in Green’s function formalism as well as known theoretical descriptions of excitations of illuminated matter [1–44]. Their additional expansion from a point-to-point approximation to an arbitrary volume-to-point and volume-to-volume formulation is achieved by employing statistically streamlined Huygens’ and superposition principles by means of geometric probability theory [51–53].
In this formulation, elementary terms are supposed to be algebraically linear in nature allowing them to be combined, like building blocks, through linear superpositions and temporal convolutions. Sources, wave propagation functions and material displacements are treated with respect to their temporal t, directional , and either spatial or areal dependencies. Temporal convolution of two functions is represented by an asterisk symbol between them: , as per common engineering convention.

Waveform transition simulations
In order to present the source enlargement transition as realistically as possible, the waveforms are simulated on a plane-parallel fused silica (SiO2) glass plate. Its physical properties are taken as: thickness , mass density , Young’s modulus , Poisson’s ratio , specific heat , and linear thermal expansion coefficient , making the propagation velocity of primary (P) waves and of secondary (S) waves .

br Patients and methods br Results In this cohort

Patients and methods

Results
In this cohort of 2,451 patients with primary T1G3, information on treatment with Connaught or TICE was available in 18 of 23 centers with 2,099 patients: 957 on Connaught and 1,142 on TICE. Maintenance BCG was given in 765 patients (36%), 560 of 957 patients (59%) on Connaught, and 205 of 1,142 patients (18%) on TICE. The distribution of patient and tumor characteristics is given in Table 1. More patients on TICE had multiple tumors, large tumors, restaging TURs, and 1 or more adverse risk factors for survival. Fewer TICE patients received maintenance.
Median follow-up was 5.2 year with a maximum follow-up of 18.7 year. The number of patients who recurred, progressed and died is summarized in Tables 2-4.

Discussion
Why is Connaught better when no maintenance is given whereas TICE seems to be better with longer treatment? Mice experiments from Rentsch showed a stronger immune response to Connaught than to TICE BCG [2]. This might explain the initial advantage of Connaught. However, we also know that immunotherapy, in cyclosporin to chemotherapy, is more likely to have an optimal biologically effective dose than a maximal effective dose. This, for example, was shown for intravesical BCG by de Reijke et al. [6]. Looking at urinary interleukin (IL)-2 kinetics, IL-2 tended to be higher during the first course and lower during the second and third course of BCG, suggesting a decreasing immune response with time. Combining these findings, one might hypothesize that Connaught reaches an earlier cumulative optimal dose and clinical effect as compared with TICE because of a stronger immune response. On the contrary, Connaught might lose some of its efficacy during maintenance therapy when TICE has reached its optimum.
Without maintenance, our lower risk of recurrence on Connaught is in line with the study by Rentsch et al. [2] who reported a significantly higher 5-year RFS rate, 74% (62.8%–87.2%) for Connaught compared to 48% (35.5%–65.1%) for TICE, P = 0.01. Their 5-year progression rates were 5.9% for Connaught and 12.9% for TICE (P = 0.34). In a multivariate analysis, BCG strain remained the only significant variable for recurrence (HR 2.91). Their mice experiments showed less TICE bacilli in lymph nodes and a stronger immune response to Connaught in similar numbers of live bacilli in both strains. It is noteworthy that the increased immune response in the bladder did not cause more local bladder symptoms. Connaught patients had even less dysuria, 13%, vs. 30% with TICE, P = 0.015. Limitations of their study are the low patient numbers (142 vs. a goal of 300) and the long recruitment period (12y).
Only a few studies have previously studied different BCG strains. Kaisary [7] compared BCG Glaxo and BCG Pasteur, initiated because results with BCG in Great Britain were disappointing. In this pilot study with 21 patients, results between the strains were similar.
In a 1994 Medical Research Council randomized marker lesion study, Fellows et al. [8] compared BCG Pasteur and Evans BCG. In 99 patients, all papillary tumors, but one, were resected and a course of 6 BCG instillations was given. In 51 eligible patients on Evans BCG, 27 (53%) still had a marker lesion or lesions at other sites at the 3 months evaluation compared with 16 (37%) of 46 eligible patients in the Pasteur group. The difference was only “statistically suggestive.”
In 1995, a Dutch study compared 6 weeks of BCG TICE, 6 weeks of BCG RIVM, and 6 months of mitomycin-C in 437 patients with NMIBC [3]. The 5-year recurrence-free rates with BCG TICE were the lowest (36±5%) and significantly less than with mitomycin-C (57±5%), P = 0.01. The 5-year recurrence-free rates with BCG RIVM were also better (54±5%) than those with TICE BCG, but the difference was not statistically significant. So again, results with BCG TICE were suboptimal without maintenance.