MRI monitoring of heating produced by ultrasound absorption in the skull: in vivo study in pigs.

The purpose of this study was to test the utility of MR thermometry for monitoring the temperature rise on the brain surface and in the scalp induced by skull heating during ultrasound exposures. Eleven locations in three pigs were targeted with unfocused ultrasound exposures (frequency = 690 kHz; acoustic power = 8.2-16.5 W; duration = 20 s). MR thermometry (a chemical shift technique) showed an average temperature rise in vivo of 2.8 degrees C +/- 0.6 degrees C and 4.4 degrees C +/- 1.4 degrees C on the brain surface and scalp, respectively, at an acoustic power level of 10 W. The temperature rise on the scalp agreed with that measured with a thermocouple probe inserted adjacent to the skull (average temperature rise = 4.6 degrees C +/- 1.0 degrees C). Characterization of the transducer showed that the average acoustic intensity was 1.3 W/cm(2) at an acoustic power of 10 W. The ability to monitor the temperature rise next to the skull with MRI-based thermometry, as shown here, will allow for safety monitoring during clinical trials of transcranial focused ultrasound.     

The effect of blood perfusion rate on the temperature distributions induced by multiple, scanned and focused ultrasonic beams in dogs' kidneys in vivo

The effect of blood perfusion rate on the temperature distribution during scanned, focused ultrasound hyperthermia was investigated using an in vivo dog kidney model. The results showed that the ultrasound beams could penetrate through the body wall without severe distortion, and that they could be used to induce controlled temperature elevations in the target volume. The blood perfusion rate of the heated tissue significantly modified the temperature distribution and the temperatures achieved in the kidney with no flow were about five times higher than in the case with full flow for the same applied acoustic power. It was also demonstrated that the power deposition pattern produced by scanned focused ultrasonic fields could be modified to give an acceptable temperature distribution in different perfusion situations. Similar trends were also obtained by using the bioheat transfer equation to simulate the experiment. Both the magnitude of the temperature elevations and the effect of perfusion on the temperature distributions obtained in the experiments were in agreement with the simulations. The main difference occurred at high perfusion rates where the experiments showed significant temperature elevation outside of the scanned volume and the simulation results predicted hardly any temperature increase 5 mm outside the scan. These observations indicate that both the theoretical power calculation programme and the temperature simulations will have value in the design of optimal heating systems, treatment planning and in the retrospective of the achieved temperature distributions.     

The construction and assessment of lenses for local treatment of malignant tumours by ultrasound

A simple method to build ultrasound lenses from araldite has been developed. The focussing properties of these lenses as a function of sonic frequency and lens diameter were studied using a computer model. The optimum frequency and diameter of these lenses were found to be around 1 MHz and between 40 and 60 mm respectively, for deep tissue heating. The stability of the power output as well as the temperature distributions produced in vitro and in vivo have also been studied. It appears to be possible to produce larger temperature elevations near the acoustical focus than near the skin surface in vivo. Therefore the lenses seem to be suitable for local cancer treatment.     

Thiopentone pharmacokinetics during cardiopulmonary bypass with a nonpulsatile or pulsatile flow

To evaluate possible factors affecting the pharmacokinetics of thiopentone during cardiopulmonary bypass (CPB), the present study was undertaken in patients scheduled for coronary artery bypass grafting and with in vitro experiments. The effects of nonpulsatile and pulsatile flow during CPB on the distribution and elimination of thiopentone were compared in 30 patients anaesthetized with fentanyl. The initial rapid phases of distribution of thiopentone were studied in 17 patients undergoing a nonpulsatile or pulsatile perfusion, to whom thiopentone 6 mg/kg was given as a rapid intravenous bolus during CPB. In order to study later distribution and early elimination of thiopentone, 13 patients perfused with a nonpulsatile or pulsatile flow received 6 mg/kg of the drug as a 15-min intravenous infusion before CPB. No differences in the pharmacokinetic parameters characterizing distribution and elimination of thiopentone were found between the patients undergoing nonpulsatile or pulsatile perfusion. As measured in 10 of the patients receiving the drug before the institution of CPB, no difference in plasma thiopentone level was observed in blood samples drawn simultaneously from a radial arterial cannula and a pulmonary artery catheter before, during and after CPB. This suggests that thiopentone is not sequestered in lungs during CPB. In vitro binding of thiopentone to the CPB equipment was studied in 6 experiments using a closed circuit. After a 60-min circulation time, only 50% of the predicted thiopentone level was recovered from the perfusate. It is concluded that replacing a nonpulsatile perfusion with a pulsatile one has no effect on the distribution and elimination of thiopentone in patients undergoing CPB. During CPB, thiopentone is sequestered in the extracorporeal circuit but not in the lungs.     

Intracellular Delivery of Bak BH3 Peptide by Microbubble-Enhanced Ultrasound

Purpose. To investigate the possibility of intracellular delivery of Bak BH3 peptide using sonoporation effect by microbubble-enhanced ultrasound.Methods. HeLa and BJAB cells were exposed to 1.696-Mhz focused ultrasound with 2% microbubble contrast agents (OPTISON®). Cell-impermeable calcein was used as an indicator for successful sonoporation, and propidium iodide staining was used for cell viability assessment. Peptides were also exposed to ultrasound with OPTISON® and analyzed with mass spectrometry for evaluation of stability under ultrasound exposure. The effect of transduced Bak BH3 peptide was evaluated by the cell viability of successfully sonoporated cells.Results. Bak BH3 peptides did not undergo mechanical degradation with microbubble-enhanced ultrasound exposure. With the increase of acoustic energy exposure, the sonoporation efficiency saturated both in BJAB and HeLa cells, while direct cell death rate by ultrasound exposure tended to increase. When BJAB cells were treated with 100 M Bak BH3 peptides, and ultrasound exposure with ultrasound contrast agents (OPTISON®), an increased 35% cell death was confirmed. On the other hand, although HeLa cells had a similar trend, they failed to exhibit statistical significance.Conclusions. Our results suggest that microbubble-enhanced focused ultrasound peptide transduction is possible. Further optimization of ultrasound exposure conditions may be necessary.     

Heart rate variability is related to training load variables in interval running exercises

Overload principle of training states that training load (TL) must be sufficient to threaten the homeostasis of cells, tissues, organs and/or body. However, there is no “golden standard” for TL measurement. The aim of the present study was to investigate if post-exercise heart rate variability (HRV) could be used to evaluate TL of interval running exercises with different intensities and durations. Thirteen endurance-trained men (35 ± 5 years) performed MO₂₅₀ [moderate intensity, 2 × 6 × 250 m/rec 30 s/5 min at 85% of the maximal velocity of the graded maximal test (V _max)], MO₅₀₀ (2 × 3 × 500 m/rec 1 min/5 min at 85% V _max) and HI₂₅₀ (high intensity, 2 × 6 × 250 m/rec 30 s/5 min at 105% V _max) interval exercises on a treadmill. HRV was analyzed during rest, exercise and immediate 15 min recovery. Fast recovery of LFP (P < 0.001), HFP (P < 0.01) and TP (P < 0.01) occurred during the first two recovery minutes after each exercise. Strong negative correlations (P < 0.01) were found between post-exercise HRV and perceived exertion as well as excess post-exercise oxygen consumption. Post-exercise HRV differentiated interval exercises of equal work, but varying intensity or distance of running bout. The results of the present study suggest that immediate post-exercise HRV may offer objective information on TL of interval exercises with different bout durations and intensities.     

Improved Anti-Tumor Effect of Liposomal Doxorubicin After Targeted Blood-Brain Barrier Disruption by MRI-Guided Focused Ultrasound in Rat Glioma

The blood-brain barrier (BBB) inhibits the entry of the majority of chemotherapeutic agents into the brain. Previous studies have illustrated the feasibility of drug delivery across the BBB using focused ultrasound (FUS) and microbubbles. Here, we investigated the effect of FUS-enhanced delivery of doxorubicin on survival in rats with and 9L gliosarcoma cells inoculated in the brain. Each rat received either: (1) no treatment (control; N = 11), (2) FUS only (N = 9), (3) IV liposomal doxorubicin (DOX only; N = 17), or (4) FUS with concurrent IV injections of liposomal doxorubicin (FUS+DOX; N = 20). Post-treatment by magnetic resonance imaging (MRI) showed that FUS+DOX reduced tumor growth compared with DOX only. Further, we observed a modest but significant increase in median survival time after a single treatment FUS+DOX treatment (p = 0.0007), whereas neither DOX nor FUS had any significant impact on survival on its own. These results suggest that combined ultrasound-mediated BBB disruption may significantly increase the antineoplastic efficacy of liposomal doxorubicin in the brain.     

Focused ultrasound surgery in oncology: overview and principles

Focused ultrasound surgery (FUS) is a noninvasive image-guided therapy and an alternative to surgical interventions. It presents an opportunity to revolutionize cancer therapy and to affect or change drug delivery of therapeutic agents in new focally targeted ways. In this article the background, principles, technical devices, and clinical cancer applications of image-guided FUS are reviewed.