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The diagnostic contribution of 2-D shear-wave elastography (SWE) in management of superficial lymph nodes (LNs) of any origin was evaluated in 222 patients referred for needle core biopsy. Each patient underwent conventional B-mode/Doppler ultrasound examinations (conventional ultrasound) and SWE. Quantitative SWE parameters and qualitative SWE map features were extracted. Carcinomas were found to be significantly stiffer than benign LNs (29.5 ± 32.3 kPa vs. 6.7 ± 12.3 kPa). Lymphomas exhibited intermediate stiffness (11.4 ± 5.2 kPa). Qualitative SWE analysis provided color patterns specific to histopathology (stiff rim, nodular and undetermined patterns related to malignancy and blue pattern to benignity). Adding SWE to conventional ultrasound improved the sensitivity of LN diagnosis (from 81.1% to 92.0%) but decreased its specificity (from 73.2% to 67.6%) because of the high prevalence of lymphomas compared with carcinomas. Inter-observer agreement for quantitative SWE was good (intra-class correlation coefficient = 0.82) as was inter-observer diagnostic agreement for qualitative SWE (κ = 0.65). LN location and histology type were found to influence the reported diagnostic performance of SWE. [ABSTRACT FROM AUTHOR]

Polymer nanoparticles and microparticles have been used primarily for drug delivery. There is now growing interest in further developing polymer-based solid cavitation agents to also enhance ultrasound imaging. We previously reported on a facile method to produce hollow poly(lactic-co-glycolic acid) (PLGA) microparticles with different diameters and degrees of porosity. Here, we investigate the cavitation response from these PLGA microparticles with both therapeutic and diagnostic ultrasound transducers. Interestingly, all formulations exhibited stable cavitation; larger porous and multicavity particles also provided inertial cavitation at elevated acoustic pressure amplitudes. These larger particles also achieved contrast enhancement comparable to that of commercially available ultrasound contrast agents, with a maximum recorded contrast-to-tissue ratio of 28 dB. Therefore, we found that multicavity PLGA microparticles respond to both therapeutic and diagnostic ultrasound and may be applied as a theranostic agent. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis is characterized by a defective, leaky and fragile microvascular construction, and microbubble-enhanced ultrasound (MEUS) with high-pressure amplitude is capable of disrupting tumor microvasculature and arresting blood perfusion. In this study, we tried to investigate whether the blood perfusion of a malignant tumor can be characteristically interrupted by combining microbubbles and diagnostic ultrasound (US). Twenty-nine Sprague-Dawley (SD) rats with subcutaneous Walker 256 tumors and seven healthy SD rats were included. Fifteen tumors were treated by MEUS, which combined constant microbubble injection and 20 episodes of irradiation by diagnostic US (i.e., acoustic radiation force impulse [ARFI] imaging). The other 14 tumors were treated by ARFI or sham US only. Seven skeleton muscles from healthy SD rats were also treated with MEUS, serving as the control. Contrast-enhanced ultrasound (CEUS) was performed before and after all treatments. The blood perfusion of the tumor MEUS group showed a significant drop immediately after treatment, followed by a quick, incomplete perfusion recovery within 10-20 min. The visual perfusion scoring result was consistent with the quantitative analysis by CEUS peak intensity. However, there were no significant perfusion changes in the tumor control groups or the muscle control group. Histologic examination found severe microvascular disruption and hemorrhage in the MEUS-treated tumors but not in the control groups. Therefore, the treatment combining diagnostic US and microbubbles can specifically decrease or interrupt the blood perfusion of Walker 256 tumors, which could be a potential new imaging method for diagnosing malignant tumors. [ABSTRACT FROM AUTHOR]

Knowledge of the acoustic attenuation characteristics of the chest wall is necessary to estimate the acoustic exposure at the pleural surface during lung ultrasound and is useful in the prediction of bio-effects (e.g., pulmonary capillary hemorrhage) and the development of safe, effective lung imaging. Currently, this property is not well characterized in humans. The aim of this work was to characterize ultrasonic attenuation in human chest wall such that the ultrasound exposures of the lung can be estimated for clinically relevant conditions. In this study, we experimentally measured ultrasound transmitted through the intercostal tissue of 15 human cadaver chest wall samples relative to ultrasound transmitted through saline to determine attenuation coefficients for each sample. A GE Vivid 7 diagnostic ultrasound machine (GE Vingmed, Horten, Norway) and 3 S and 5 S phased array probes were used at center frequencies from 1.6 to 5 MHz. The chest wall samples varied in thickness from 2.3-5.5 cm with a median thickness of 3.8 cm. The frequency-normalized attenuation coefficient was approximately 1.44 dB/cm/MHz based on a linear best fit through all attenuation measurements. Attenuation characteristics varied appreciably between samples, and the sample-averaged linear attenuation coefficient was 1.43 ± 0.32 (mean ± standard deviation) dB/cm/MHz. This attenuation is higher than that previously measured in mammalian chest wall samples (1.1-1.3 dB/cm/MHz for mice and rats) and is much greater than that used by the mechanical index (0.3 dB/cm/MHz). Mechanical index values calculated using saline values de-rated by 0.3 dB/cm/MHz were up to 1.2 MPa/MHz1/2 greater than those calculated using the measured through-tissue ultrasound waves. We conclude that the mechanical index overestimates exposures for lung ultrasound and thus may not be an appropriate dosimetry metric for pulmonary ultrasound. [ABSTRACT FROM AUTHOR]

Pulmonary capillary hemorrhage (PCH) has been found in mammalian lungs exposed to diagnostic ultrasound (DUS), although the mechanism is poorly understood. This work investigates acoustic atomization and fountains at liquid-air interfaces subjected to DUS, which has been suggested as a possible PCH damage mechanism. Primarily using a SuperSonic Imagine Aixplorer DUS machine (SuperSonic Imagine, Aix-en-Provence, France), blood and water surfaces were excited in vitro by DUS and recorded with a high-speed camera. The surface was driven by B-mode, color Doppler, pulsed Doppler, and shear wave elastography imaging modes with center frequencies from 5.0-7.2 MHz and mechanical indexes (MI) up to 1.7. Fountains and atomization were only observed for SWE, for MI as low as 1.0. A comparison of the SWE waveforms with the surface dynamics suggests that fountains and atomization were driven by push-pulses and depended on pulse duration and intensity. However, we conclude that atomization and fountaining are unlikely primary mechanisms behind all DUS-induced PCH because neither phenomenon occurred for traditional diagnostic imaging modes. [ABSTRACT FROM AUTHOR]

Abstract The purpose of our study was to evaluate the diagnostic accuracy of the ultrasound-guided attenuation parameter (UGAP) for the detection of hepatic steatosis in comparison with the controlled attenuation parameter (CAP), using histopathology as the reference standard. We prospectively analyzed 163 consecutive chronic liver disease patients who underwent UGAP, CAP, computed tomography and a liver biopsy on the same day between April 2016 and July 2017. Radiofrequency signals corresponding to the images were compensated by the reference signal previously measured from the uniform phantom with known attenuation (0.44 dB/cm/MHz). The attenuation coefficient was calculated from the signals' decay slope. The median attenuation coefficient values in patients with S0 (n = 62), S1 (n = 63), S2 (n = 23) and S3 grade (n = 15) were 0.485, 0.560, 0.660 and 0.720, respectively. Significant correlations were found between attenuation coefficient and percentage steatosis, CAP values and liver-to-spleen computed tomography attenuation ratio (p < 0.001). The areas under the receiver operating characteristic curve of UGAP for identifying ≥S1, ≥S2 and ≥S3 were 0.900, 0.953 and 0.959, respectively, which were significantly better than the results obtained with CAP for identifying ≥S2 and ≥S3. In conclusion, UGAP had high diagnostic accuracy for detecting hepatic steatosis in patients with chronic liver disease [ABSTRACT FROM AUTHOR]

The goal of our research was to quantify the placental vascularity in 3-D at 11-13 + 6 wk of pregnancy at precise distances from the utero-placental interface (UPI) using 3-D power Doppler ultrasound. With this automated image analysis technique, differences in vascularity between normal and pathologic pregnancies may be observed. The algorithm was validated using a computer-generated image phantom and applied retrospectively in 143 patients. The following features from the PD data were recorded: The number of spiral artery jets into the inter-villous space, total geometric and PD area. These were automatically measured at discrete millimeter distances from the UPI. Differences in features were compared with pregnancy outcomes: Pre-eclamptic versus normal, all small-for-gestational age (SGA) to appropriate-for-gestational age (AGA) patients and AGA versus SGA in normotensives (Mann-Whitney). The Benjamini-Hochberg procedure was used (false discovery rate 10%) for multiple comparison testing. Features decreased with increasing distance from the UPI (Kruskal-Wallis test; p <0.001). At 2- 3 mm from the UPI, all features were smaller in pre-eclamptic compared with normal patients and for some in SGA compared with AGA patients (p <0.05). For AGA versus SGA in normotensive patients, no significant differences were found. Number of jets measured at 2-5 mm from the UPI did not vary because of the position of the placenta in the uterus (ANOVA; p > 0.05). This method provides a new in-vivo imaging tool for examining spiral artery development through pregnancy. Size and number of entrances of blood flow into the UPI could potentially be used to identify high-risk pregnancies and may provide a new imaging biomarker for placental insufficiency. [ABSTRACT FROM AUTHOR]

We sought to explore mechanistically how intermittent high-mechanical-index (MI) diagnostic ultrasound impulses restore microvascular flow. Thrombotic microvascular obstruction was created in the rat hindlimb muscle of 36 rats. A diagnostic transducer confirmed occlusion with low-MI imaging during an intravenous microbubble infusion. This same transducer was used to intermittently apply ultrasound with an MI that produced stable or inertial cavitation (IC) for 10 min through a tissue-mimicking phantom. A nitric oxide inhibitor, L-Nω-nitroarginine methyl ester (L-NAME), was pre-administered to six rats. Plateau microvascular contrast intensity quantified skeletal microvascular blood volume, and postmortem staining was used to detect perivascular hemorrhage. Intermittent IC impulses produced the greatest recovery of microvascular blood volume (p < 0.0001, analysis of variance). Nitric oxide inhibition did not affect the skeletal microvascular blood volume improvement, but did result in more perivascular hemorrhage. IC inducing pulses from a diagnostic transducer can reverse microvascular obstruction after acute arterial thromboembolism. Nitric oxide may prevent unwanted bio-effects of these IC pulses. [ABSTRACT FROM AUTHOR]

The mechanical index (MI) is a theoretical exposure parameter for cavitational bio-effects of diagnostic ultrasound. The theory for the MI assumed that bubbles of all relevant sizes exist in tissue, a condition that is approximated for tissues that include a microbubble contrast agent. Therefore, the MI should allow science-based safety guidance for contrast-enhanced diagnostic ultrasound. However, theoretical predictions of bio-effects thresholds based on the MI typically do not concur with the frequency dependence of experimentally measured thresholds for bio-effects. For example, experimental thresholds for glomerular capillary hemorrhage in rats infused with contrast microbubbles increased approximately linearly with frequency, whereas the MI predicted a square root dependence. Here, cavitation thresholds were computed for linear versions of the acoustic pulses used in that study assuming bubbles containing either air, C3F8, or a 1:1 mixture of the two and surrounded by either blood or kidney tissue. Although no single threshold criterion was successful, combining results for one criterion that maximized circumferential stress in the capillary wall with another that ensured an inertial collapse produced thresholds that were consistent with experimental data. This suggests that a contrast-specific safety metric may be achieved following validation of this two-criterion model. [ABSTRACT FROM AUTHOR]

Diagnostic ultrasound probes are one of the most stressed components of ultrasound system. A faulty probe can lead to misdiagnosis. Therefore, quality assurance (QA) of ultrasound probes is becoming a major concern. The disadvantages of complex QA methods are high cost of the equipment required for probe analysis and time-consuming nature of the process. We used an ultrasound system that allows the required elements to be switched off. We set the acoustic power to the highest available value in order to maximize heating of the elements. Other imaging parameters corresponded to usual B-mode settings. The evaluation method is based on the examination of a linear probe operating in air and free of gel. Heating of the probe was captured by an infrared (IR) camera with a resolution of 640 x 480 pixels. The IR camera is equipped with uncooled microbolometer detectors. The acquisition time was 10 seconds (2 seconds with an inactive probe to capture noise and an additional 8 seconds with the active probe to investigate heating). Using this method, we can detect single element dropouts across the probe apart from 5 elements at the edge. The moving aperture causes that the elements at the edges are heated to lower temperature than the elements in the middle. The parts of the probe with non-uniform heating require a more detailed analysis. The method has been validated on convex and phased array probes with equal success. This method seems to be useful for quality assurance of ultrasound probes. The main advantages of method are time saving (10-second measurement + fast analysis), no need for special equipment (a commercially available IR camera can be used for various types of probes) and reliability. The only limitation is the spatial resolution of the camera. Future research will focus on the applicability of this method to other types of ultrasound probe failures [ABSTRACT FROM AUTHOR]

High-intensity focused ultrasound (HIFU) is rapidly gaining acceptance as a non-invasive method for soft tissue tumor ablation, but improvements in the methods of treatment delivery, planning and monitoring are still required. Backscatter temperature imaging (BTI) uses ultrasound to visualize heating-induced echo strain and may be used to indicate the position of the HIFU focal region using low-power “sub-lesioning” exposure. The technique may also provide a quantitative tool for assessing the efficacy of treatment delivery if apparent strain measurements can be related to the underlying temperature rise. To obtain temperature estimates from strain measurements, the relationship between these variables has to be either measured or otherwise assumed from previous calibrations in similar tissues. This article describes experimental measurements aimed at deriving the relationship between temperature rise and apparent strain in the laboratory environment using both ex vivo bovine liver tissue samples and normothermically perfused porcine livers. A BTI algorithm was applied to radiofrequency ultrasound echo data acquired from a clinical ultrasound scanner (Z.One, Zonare Medical Systems, Mountain View, CA, USA) where the imaging probe was aligned with the focal region of a HIFU transducer. Temperature measurements were obtained using needle thermocouples implanted in the liver tissue. A series of “non-ablative” HIFU exposures giving peak temperatures below 10°C were made in three separate ex vivo bovine livers, yielding an average strain/temperature coefficient of 0.126 ± 0.088 percentage strain per degree Celsius. In the perfused porcine livers at a starting temperature of 38°C (normal body temperature) the strain/temperature coefficients were found to be 0.040 ± 0.029 percentage strain per degree Celsius. The uncertainty in these results is directly linked to the precision of the strain measurement, as well as the naturally occurring variance between different tissue samples, indicating that BTI may lack the accuracy required to be implemented successfully in practice as a quantitative treatment planning technique at a sub-lesioning exposure level. This is because, to be of use in treatment planning, temperature-rise estimates may require an accuracy greater (<10%) than that offered by BTI measurement. BTI may, however, still play a role in ensuring the correct positioning of the focal region and as a treatment monitoring modality capable of detecting an increased rate of heating in tissue after HIFU ablation. [ABSTRACT FROM AUTHOR]

Abstract: Ultrasound-targeted microbubble destruction (UTMD) takes advantage of transiently increased capillary permeability to enhance the release of tumor-specific drugs from blood vessels into sonicated tumor tissues. However, the application of focused ultrasound is limited because of the lack of an appropriate image-monitoring system. In this study, hepatoma-bearing Sprague-Dawley rats were insonicated with low-frequency diagnostic ultrasound and injected with Evans Blue (EB) dye and microbubbles through their tail veins to test changes in capillary permeability. We studied how the mechanical index, sonication duration and the injected microbubble (MB) concentration affect the hepatoma vascular permeability by quantitatively evaluating the EB delivery efficiency. Confocal laser scanning microscopy was used to observe the deposition of red fluorescence–dyed EB in tumor tissues. In addition, P-selectin, a type of biochemical marker that reflects vascular endothelial cell activation, was identified using an immunoblotting analysis. The experimental results reveal that EB delivery efficiency in tumor tissues was greater in groups with the diagnostic ultrasound–mediated UTMD (8.40 ± 0.71 %ID/g) than in groups without UTMD (1.73 ± 0.19 %ID/g) and EB delivery efficiency could be affected by MI, sonication duration and MB dose. The immunoblotting analysis indicates that diagnostic ultrasound–induced UTMD results in the vascular endothelial cell activation to increase capillary permeability, justifying the high quantity of EB deposited in tumor tissues. [Copyright &y& Elsevier]

Abstract: Vascular ultrasound can provide quick and reliable diagnosis of arterial bleeding but it requires trained and experienced personnel. Development of automated sonographic bleed detection methods would potentially be valuable for trauma management in the field. We propose a detection method that (1) measures blood flow in a trauma victim, (2) determines the victim’s expected normal limb arterial flow using a power law biofluid model where flow is proportional to the vessel diameter taken to a power of k and (3) quantifies the difference between measured and expected flow with a novel metric, flow split deviation (FSD). FSD was devised to give a quantitative value for the likelihood of arterial bleeding and validated in human upper extremities. We used ultrasound to demonstrate that the power law with k = 2.75 appropriately described the normal brachial artery bifurcation geometry and adequately determined the expected normal flows. Our metric was then applied to three-dimensional (3-D) computational models of forearm bleeding and on dialysis patients undergoing surgical construction of wrist arteriovenous fistulas. Computational models showed that larger sized arterial defects produced larger flow deviations. FSD values were statistically higher (paired t-test) for arms with fistulas than those without, with average FSDs of 0.41 ± 0.12 and 0.047 ± 0.021 (mean ± SD), respectively. The average of the differences was 0.36 ± 0.12 (mean ± SD). [Copyright &y& Elsevier]

Abstract: Ultrasound targeted microbubble destruction has succeeded in delivering drugs and genes. This study was designed to explore characteristics of ultrasound targeted microbubble destruction using short-pulsed diagnostic ultrasound. Canine thyroid adenocarcinoma cells were exposed to short-pulsed diagnostic ultrasound in the presence of cis-diamminedichloroplatinum (II) (cisplatin) and ultrasound contrast agent Sonazoid® microbubbles. The cytotoxic effect of cisplatin was enhanced by short-pulsed diagnostic ultrasound and microbubbles. Incubation time with microbubbles influenced the cytotoxic effect of cisplatin. However, exposure duration did not affect the cytotoxic effect of cisplatin. Therefore, short-pulsed diagnostic ultrasound may activate microbubbles near cells and deliver cisplatin into cells. In addition, activation of microbubbles may be concluded in a short time. Our results suggest that short exposure duration could be potentially sufficient to induce efficient drug delivery by ultrasound targeted microbubble destruction using short-pulsed diagnostic ultrasound. [Copyright &y& Elsevier]

Abstract: This guidance is intended to encourage best practice among researchers into ultrasound bio-effects in terms of how they determine and report the exposure conditions used in their studies. It covers both diagnostic and therapeutic applications of ultrasound and is intended to be useful to the researchers themselves, to the review boards of ethical and funding committees and to the editors and reviewers of scientific journals. Recommendations are made for reporting formats, depending on the information available, and level of the study. (E-mail: Gail.terHaar@icr.ac.uk) [Copyright &y& Elsevier]

Abstract: Over the years, there has been a substantial increase in acoustic exposure in diagnostic ultrasound as new imaging modalities with higher intensities and frame rates have been introduced; and more electronic components have been packed into the probe head, so that there is a tendency for it to become hotter. With respect to potential thermal effects, including those which may be hazardous occurring during ultrasound scanning, there is a correspondingly growing need for in vivo techniques to guide the operator as to the actual temperature rise occurring in the examined tissues. Therefore, an in vivo temperature estimator would be of considerable practical value. The commonly-used method of tissue thermal index (TI) measurement with a hydrophone in water could underestimate the actual value of TI (in one report by as much as 2.9 times). To obtain meaningful results, it is necessary to map the temperature elevation in 2-D (or 3-D) space. We present methodology, results and validation of a 2-D spatial and temporal thermal strain ultrasound temperature estimation technique in phantoms, and its apparently novel application in tracking the evolution of heat deposition at diagnostic exposure levels. The same ultrasound probe is used for both transmission and reception. The displacement and thermal strain estimation methods are similar to those used in high-intensity focused ultrasound thermal monitoring. The use of radiofrequency signals permits the application of cross correlation as a similarity measurement for tracking feature displacement. The displacement is used to calculate the thermal strain directly related to the temperature rise. Good agreement was observed between the temperature rise and the ultrasound power and scan duration. Thermal strain up to 1.4% was observed during 4000-s scan. Based on the results obtained for the temperature range studied in this work, the technique demonstrates potential for applicability in phantom (and possibly in vivo tissue) temperature measurement for the determination of TI. (E-mail: Haidong.Liang@UHBristol.nhs.uk) [Copyright &y& Elsevier]

Abstract: The thermal index (TI) displayed on the screens of most modern diagnostic ultrasound machines is linearly proportional to the absorbed power or, equivalently, to the in-situ intensity or temperature rise. Users are instructed to interpret the TI as a “relative indication of bioeffect risk.” The thermal dose is a well-known empirical relationship between the temperature T of a biological system and the time t needed for that temperature to induce a deleterious effect. For any two temperatures, T 1 and T 2, and the corresponding times t 1 and t 2, required to produce the same level of effect, this general relation holds: t 1/t 2 = R T 2 −T 1 , where R is the thermal normalization constant. Hence, it is experimentally determined that the rate of induction, or risk, of a thermal effect increases exponentially with temperature. Because exponential relationships are not intuitive to many users, there is a significant potential for underestimation of the thermal risk associated with exposure to diagnostic ultrasound. To better quantify this risk and thereby make the displayed information more useful, the current linear display of the calculated value of the thermal index, i.e., of TIcur, should be altered to an exponential form based on the thermal dose and representing the excess risk associated with the exposure: TInew = (R TIcur − 1)/(R − 1). This expression has the advantage that for the usual choice of R = 4 for T ≤ 43° C, TInew ∼ TIcur in the range most often seen onscreen, i.e., TIcur < 1.2, minimizing any confusion during a transition from TIcur to TInew. For the relatively rare but potentially much more serious circumstances when TIcur > 3.5, the displayed TInew ≫ TIcur, consistent with empirical observations of the likelihood of harm. Additional advantages also obtain. (E-mail: cchurch@olemiss.edu) [Copyright &y& Elsevier]

Abstract: Echogenic liposomes (ELIP) are submicron-sized phospholipid vesicles that contain both gas and fluid. With antibody conjugation and drug incorporation, these liposomes can be used as novel targeted diagnostic and therapeutic ultrasound contrast agents. The utility of liposomes for contrast depends upon their stability in an acoustic field, whereas the use of liposomes for drug delivery requires the liberation of encapsulated gas and drug payload at the desired treatment site. The objective of this study was twofold: (1) to characterize the stability of liposome echogenicity after reconstitution and (2) to quantitate the acoustic destruction thresholds of liposomes as a function of peak rarefactional pressure (Pr), pulse duration (PD) and pulse repetition frequency (PRF). The liposomes were insonified in an anechoic sample chamber using a Philips HDI 5000 diagnostic ultrasound scanner with a L12-5 linear array. Liposome stability was evaluated with 6.9-MHz fundamental and 4.5-MHz harmonic B-mode pulses at various Pr at a fixed PRF. Liposome destruction thresholds were determined using 6.0-MHz Doppler pulses, by varying the PD with a fixed PRF of 1.25 kHz and by varying the PRF with a fixed PD of 3.33 μs. Videos or freeze-captured images were acquired during each insonation experiment and analyzed for echogenicity in a fixed region of interest as a function of time. An initial increase in echogenicity was observed for fundamental and harmonic B-mode imaging pulses. The threshold for acoustically driven diffusion of gas out of the liposomes using 6.0-MHz Doppler pulses was weakly dependent upon PRF and PD. The rapid fragmentation thresholds, however, were highly dependent upon PRF and PD. The quantification of acoustic destruction thresholds of ELIP is an important first step in their development as diagnostic and drug delivery agents. (E-mail: smitdn@email.uc.edu) [Copyright &y& Elsevier]

Abstract: One kidney of anesthetized rats was imaged by diagnostic ultrasound with contrast agent under conditions simulating both the geometry and the attenuation encountered during human perfusion imaging. Contrary to earlier predictions, glomerular capillary rupture with blood loss into Bowman’s space and proximal tubules occurred in our clinically relevant model system. Quantitative analysis of histologic sections showed that 37 ± 5% of the glomeruli at the center of the scan plane had blood cells in Bowman’s space after imaging for 1 min with 1.8 MPa (mechanical index equivalent, MIe = 1.5) with a 1 s image trigger interval during IV injection of 10 μl/kg/min of Definity® contrast agent (as recommended by the manufacturer). This percentage decreased rapidly with decreasing peak rarefactional pressure amplitude to an apparent threshold of 0.73 MPa (MIe = 0.6). The percentage of glomeruli with hemorrhage decreased in proportion to dose when reduced below the recommended value, but leveled-off at doses above it. The percentage of glomerular hemorrhage increased with increasing numbers of image exposures, with an initial rate of 1.1% per image. The glomerular hemorrhage also depended on the frame trigger interval with no hemorrhage evident for continuous imaging but a maximal effect for trigger intervals greater than about 1 s. These results indicated that there is a potential for clinical diagnostic ultrasound with contrast agent to induce glomerular hemorrhage. (E-mail: douglm@umich.edu) [Copyright &y& Elsevier]

Abstract: The potential for enhancement of the metastatic spread of cells from mouse melanoma tumors was examined for exposure to diagnostic ultrasound (DUS) and high-amplitude ultrasound (HAUS) without and with ultrasound (US) contrast agent. The melanoma cell line B16-D5, which is metastatic specifically to lung, was cultured and implanted on a hind leg of female C57/bl6 mice. For DUS, tumors were scanned using 1.5-MHz harmonic B-mode imaging with 1-Hz intermittent frame triggering at 2.1 MPa (equivalent MI = 1.7) in a 37° C water bath. For HAUS, a 1.35-MHz focused transducer directed 1-ms bursts at 5 MPa to the tumor at a 1-Hz rate. A total dose of 1 mL/kg Optison® was injected during exposures. Exposure without contrast agent received the same exposure followed by the contrast agent with the US off. The primary tumor was removed surgically one day after US. Lungs were removed after four weeks for evaluation of metastases. Experiments involved exposure without and with contrast agent in groups of 20 mice. For DUS, mean counts of 0.8 ± 0.3 (standard error) and 1.3 ± 0.9 (P = 0.62) metastases were found for groups exposed without and with contrast, respectively. For HAUS, mean counts of 3.4 ± 1.2 and 5.9 ± 1.7 (P = 0.35) metastases were found for groups exposed without and with contrast, respectively. The lack of effect of DUS exposure with contrast confirms a previous finding. However, the HAUS counts and incidence were significantly larger than the DUS results (P < 0.05) in a two-way analysis of variance. This indicates a potential for HAUS to enhance metastasis. (E-mail: douglm@umich.edu) [Copyright &y& Elsevier]

Abstract: Empirical mode decomposition (EMD) is a relatively new technique used in the analysis of nonlinear and nonstationary time series. Previous signal-processing methods used for medical ultrasound have been based on the assumption of a linear time-invariant system. More recently, the technique of tissue harmonic imaging (THI) has become prevalent. This technique relies on the nonlinear propagation of the sound wave through the medium to disperse the signal energy into the harmonic frequencies of the transmitted signal. In this paper, results are presented from using EMD to process received ultrasound echo signals that have passed through nonlinear media. The Hilbert spectrum is used to demonstrate an interpretation of the physical process underlying THI that is based on the concept of intrawave frequency modulation, rather then the spreading of signal energy into harmonic frequencies. The technique of EMD is shown to be able to produce superior results to the bandpass filtering method of THI, even when the band width of the transducer was such that the second harmonic would be suppressed. (E-mail: bmd@ee.ed.ac.uk) [Copyright &y& Elsevier]

Diagnostic ultrasound (US) is reported to increase intracellular oxidative stress in vitro. Increased oxidative stress mediated ischemia-reperfusion injury in the microcirculation. To examine the effects of US in hamster cheek pouch microcirculation during baseline and ischemia and reperfusion (I/R), I/R injury was provoked in the cheek pouch under “sham” (transducer off, group 1) and active US irradiation (group 2) at baseline (15 min) and at the beginning (15 min) of the reperfusion after ischemia (30 min). US transmission was delivered in the harmonic mode (2.5 MHz) with 1.3 mechanical index (MI) and 2.0 peak negative pressure. Microvascular damage was evaluated by measuring arterial diameter, red blood cell velocity, wall shear stress, permeability, perfused capillary length and adherent leukocytes in venules. Lipid peroxides were determined in the systemic blood. US increased permeability (baseline: 0.04 ± 0.02; after US 0.30 ± 0.04, p < 0.01) and slightly decreased capillary perfusion by 7% during baseline (p < 0.01). Arteriolar diameter (35 ± 7 μm vs. 20 ± 5 μm, p < 0.05), RBC velocity (2.8 ± 0.4 mm s−1 vs. 0.75 ± 0.05 mm s−1, p < 0.05) and shear stress ( 0.76 ± 0.09 Pa vs. 0.36 ± 0.05 Pa, p < 0.05) decreased significantly after reperfusion. These parameters increased by 40, 64 and 33%, respectively after US. Leukocyte adhesion decreased by 31 % (p < 0.05) after US and lipid peroxides decreased by 26% and 51% during baseline and 15 min of reperfusion after US, respectively. In conclusion, diagnostic US increased microvascular permeability during baseline and reperfusion. Moreover, US enhanced wall shear stress and reduced oxidative stress during postischemic reperfusion; thus, increasing capillary perfusion. (E-mail: sibert@ifc.cnr.it) [Copyright &y& Elsevier]

Microvascular permeabilization, petechial hemorrhage and premature ventricular contractions (PVCs) have been demonstrated in an in vivo rat model of myocardial contrast echocardiography (MCE). The purpose of this study was to compare these effects for three US Food and Drug Administration (FDA)-approved ultrasound (US) contrast agents (US CA): Optison®, Definity® and Imagent®. Evans blue dye, an indicator of microvascular permeability, and a contrast agent were injected IV in anesthetized rats suspended in a water bath to mimic scanning depths seen in clinical echocardiology. Diagnostic US B-mode scans with 1:4 end-systolic triggering were performed at 1.7 MHz using a cardiac phased-array scanhead to provide a short axis view of the left ventricle. To elicit readily measurable effects for comparisons, relatively high doses of the agent were used (50 to 500 μL kg−1 for Optison®, 25 to 200 μL kg−1 for Imagent®, 10 to 100 μL kg−1 for Definity®). Microvascular leakage was characterized by the area of Evans blue dye coloration on the hearts and by extraction of the dye from tissue samples. The number of petechia were counted on the epicardial surface of excised hearts. PVCs were counted from ECG traces recorded with the MCE images. Neither evidence of capillary leakage nor PVCs were seen in sham animals. Based on volume dose, Definity® MCE produced more microvascular leakage, but there was no apparent difference between the three agents'' microvascular damage potential, which increased linearly with dose at low doses, when expressed in terms of the number of stabilized microbubbles. Definity® MCE resulted in fewer PVCs than the other agents. The effects increased strongly with peak rarefactional pressure amplitude, with apparent thresholds for petechiae at 0.4 MPa and for PVCs at about 1.0 MPa. These results should be of value for minimizing adverse potential in diagnosis and optimizing efficacy in therapeutic applications. (E-mail: douglm@umich.edu) [Copyright &y& Elsevier]

Gas bubbles of sufficient size to serve as cavitation nuclei may form spontaneously in tissue in regions of very low interfacial tension. In the absence of an acoustic wave or other mechanical stress, such nuclei will quickly dissolve and disappear from the medium. Under the influence of an acoustic wave, however, these microbubbles may grow to many times their initial size and then collapse violently, a process known as inertial cavitation. In this work, the in vivo energetics and dynamics of the nucleation-cavitation process were modeled by treating tissue as a homogeneous fluid. The assumption of a viscosity of 10−3 Pa s (i.e., that of water) resulted in the lowest acoustic rarefactional pressure threshold for nucleation-cavitation events, ∼4.0 MPa, which was essentially frequency-independent over the range 1 to 15 MHz. The rarefactional pressure threshold for a viscosity of 5 × 10−3 Pa s (that of blood) also was ∼4.0 MPa at 1 MHz, but the threshold for this higher viscosity increased nearly linearly with frequency above ∼5 MHz, never being more than ∼0.2 MPa below the equivalent derated peak rarefactional pressure calculated assuming MI = 1.9, the current USFDA guideline. (E-mail: cchurch@olemiss.edu) [Copyright &y& Elsevier]

A new diagnostic ultrasound (US) technique, sometimes called radiation force imaging, produces and detects motion in solid tissue or acoustic streaming in fluids via a high-intensity beam. Current models for estimating temperature rise during US exposure calculate the steady-state rise, using time-averaged acoustic output, as the worst case for safety consideration. Although valid for very short pulses, this analysis might not correspond to a worst-case scenario for the longer pulses or pulse bursts, up to hundreds of ms, used by this newer method. Models are presented to calculate the transient temperature rise from these pulse bursts for both the bone at focus and soft tissue situation. It is shown, based on accepted time-temperature dose criteria, that, for the bone at focus case and pulse lengths and intensities utilized by these methods, temperature may increase to levels that raise safety concerns. Also, regulatory aspects of this modality are analyzed in terms of the current FDA acoustic output limits for diagnostic US devices. (E-mail: bah@cdrh.fda.gov) [Copyright &y& Elsevier]

Successful clinical applications of contrast agents involve an understanding of the physical interaction of ultrasound (US) with contrast agents. This paper reviews the physical phenomena involved in these interactions and discusses the relevant theoretical background for modeling US-contrast agent interactions. Measurement techniques using US to obtain information regarding contrast agents are summarized. Illustrative clinical applications are given in the second part of the paper. Recent developments in nonlinear imaging techniques and transient techniques are reviewed. New methods, such as depletion perfusion measurement, and high-frequency applications are included. (E-mail: cheri@rrinyc.org) [Copyright &y& Elsevier]

The propagation of ultrasonic waves is nonlinear. Phenomena associated with the propagation of diagnostic ultrasound pulses cannot be predicted using linear assumptions alone. These include a progressive distortion in waveform, the generation of frequency harmonics and acoustic shocks, excess deposition of energy and acoustic saturation. These effects occur most strongly when ultrasound propagates within liquids with comparatively low acoustic attenuation, such as water, amniotic fluid or urine. Within soft tissues, similar effects occur, although they are limited by absorption and scattering. Nonlinear effects are of considerable importance during acoustic measurements, especially when these are used to predict in situ exposure. Harmonic generation may be used to create images. These offer improvements over conventional B-mode images in spatial resolution and, more significantly, in the suppression of acoustic clutter and side-lobe artifacts. B/A has promise as a parameter for tissue characterisation, but methods for imaging B/A have shown limited success. (E-mail: f.duck@bath.ac.uk) [Copyright &y& Elsevier]