MRI-guided Disruption of the Blood-brain Barrier using Transcranial Focused Ultrasound in a Rat Model

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB^1-5. The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size⁶. FUS induced BBB disruption (BBBD) is temporary and reversible⁴ and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB^2,5,7, there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment.     

Phospholipid-coated targeted microbubbles for ultrasound molecular imaging and therapy

Phospholipid-coated microbubbles are ultrasound contrast agents that, when functionalized, adhere to specific biomarkers on cells. In this concise review, we highlight recent developments in strategies for targeting the microbubbles and their use for ultrasound molecular imaging (UMI) and therapy. Recently developed novel targeting strategies include magnetic functionalization, triple targeting, and the use of several new ligands. UMI is a powerful technique for studying disease progression, diagnostic imaging, and monitoring of therapeutic responses. Targeted microbubbles (tMBs) have been used for the treatment of cardiovascular diseases and cancer, with therapeutics either coadministered or loaded onto the tMBs. Regardless of which disease was treated, the use of tMBs always resulted in a better therapeutic outcome than non-tMBs when compared in vitro or in vivo.     

The endoscopist and malignant and non-malignant biliary obstruction

Patients with biliary strictures often represent a diagnostic and therapeutic challenge, due to the site and complexity of biliary obstruction and wide differential diagnosis. Multidisciplinary decision making is required to reach an accurate and timely diagnosis and to plan optimal care. Developments in endoscopic ultrasound and peroral cholangioscopy have advanced the diagnostic yield of biliary endoscopy, and novel optical imaging techniques are emerging. Endoscopic approaches to biliary drainage are preferred in most scenarios, and recent advances in therapeutic endoscopic ultrasound allow drainage where the previous alternatives were only percutaneous or surgical. Here we review recent advances in endoscopic practice for the diagnosis and management of biliary strictures. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.     

超声介入治疗常见妇科囊性炎症包块的疗效评价

目的：比较超声引导介入治疗盆腔脓肿、输卵管积脓、输卵管积液、包裹性积液及宫颈囊肿的,临床效果,了解超声引导介入治疗常见的妇科囊性炎症包块的临床价值。方法：选取我院妇科门诊2007年1月～2011年3月收治的常见妇科囊性炎症包块共108例,其中盆腔脓肿11例、输卵管积脓19例、输卵管积液43例、盆腔包裹性积液31例、宫颈囊肿4例,给予超声实时引导抽囊液、甲硝唑冲洗治疗,治疗后3个月内复查超声评价和比较疗效。结果：盆腔脓肿、输卵管积脓、盆腔包裹性积液包块均明显缩小（12／43）或消失（29／43）,治疗有效率100％;输卵管积液包块治疗有效率95％（41／43）,宫颈囊肿均痊愈。各组间比较无统计学差异（P〉O．05）。结论：超声引导介入治疗对输卵管积脓、盆腔脓肿、盆腔包裹性积液均有显著的疗效,且治疗效果无差异,值得推广应用,代替传统的非必要的手术治疗。     

Rapporteur report: Roundup, discussion and recommendations

There is a relative paucity of recent information regarding the long-term health effects associated with exposure to ultrasound, and to infrasound and low-frequency noise (LFN). For ultrasound, further epidemiological studies are recommended, and priority should be given to studies investigating the effects of handedness and to studies assessing possible subtle effects on brain function. These studies should reflect contemporary practises in diagnostic ultrasound and have sufficiently long follow-up periods to examine the possibility of effects into late adolescence or beyond. In the absence of a non-exposed control group, it would be advisable to make comparisons between a highly exposed group with a less exposed group, and to compare groups exposed at differing gestational stages. The effects associated with ultrasound contrast agents should also be studied, and the appropriateness of the thermal index (TI) and mechanical index (MI) should be reviewed. It is recommended that animal models should be used to investigate the effects of exposure at differing gestational ages on development, and modern cellular and molecular techniques used to investigate potential mechanisms of interaction. Although explicit morphological changes have been reported following occupational and experimental exposures to infrasound and low LFN, it was recommended that a thorough review of the relevant biological and health effects literature was necessary before specific proposals could be made. Uncertainties about the characterisation of these low frequencies also indicated the need to develop appropriate measurement techniques and protocols.     

骨性关节炎的超声诊断价值

骨性关节炎是目前发病率较高的一组以关节软骨为主要病理特征的临床综合症,目前主要影像学检查方式包括:X线、CT、MRI。近年来随着超声成像技术水平和精确性的不断提高,已能够更加快捷、方便、准确的对骨性关节炎作出较明确的诊断,具有重要的临床价值。     

超声分子成像的研究进展

超声成像无创、无放射性、低成本、实时成像的优点,使其成为目前世界上应用最广的成像手段之一。特别是超声造影剂引入之后,超声成像的图像分辨率和灵敏度得到了大大提高,使超声成像在临床上得到了进一步应用。近年来,随着分子生物学和超声成像技术的不断发展,人们提出了＂超声分子成像＂的概念。它是一项结合了分子靶向造影剂和超声影像技术的能在分子水平下观察病理变化的新兴技术,目前这一技术还处于研究初期阶段。但大量临床前的研究成果已表明超声分子成像在诊断血管生成、炎症和血栓三种疾病具有很大应用前景。本文主要综述了目前常用超声造影剂的种类以及超声分子成像技术的研究现状,并对该技术进行了讨论和展望。     

Therapeutic application of ultrasound: contrast-enhanced thrombolysis in acute ST-elevation myocardial infarction; the Sonolysis study

Contrast enhancement by microbubble infusion has proven its applicability in the field of diagnostic ultrasound. Recent studies also indicate a therapeutic effect of the combined use of ultrasound and microbubbles. Results from animal studies demonstrate that diagnostic ultrasound in combination with intravenous microbubbles can dissolve thrombi. So far, this effect has never been tested in patients with an acute ST-elevation myocardial infarction (STEMI). We recently launched a pilot study in acute STEMI patients to assess safety, feasibility and efficacy of the treatment in this patient group with transthoracic three-dimensional diagnostic ultrasound and intravenous microbubbles immediately after prehospital thrombolysis, but prior to primary percutaneous coronary intervention.     

超声分子成像的研究进展

超声成像无创、无放射性、低成本、实时成像的优点,使其成为目前世界上应用最广的成像手段之一。特别是超声造影剂引入之后,超声成像的图像分辨率和灵敏度得到了大大提高,使超声成像在临床上得到了进一步应用。近年来,随着分子生物学和超声成像技术的不断发展,人们提出了"超声分子成像"的概念。它是一项结合了分子靶向造影剂和超声影像技术的能在分子水平下观察病理变化的新兴技术,目前这一技术还处于研究初期阶段。但大量临床前的研究成果已表明超声分子成像在诊断血管生成、炎症和血栓三种疾病具有很大应用前景。本文主要综述了目前常用超声造影剂的种类以及超声分子成像技术的研究现状,并对该技术进行了讨论和展望。     

Ultrasonically assisted liquefaction of lignocellulosic materials

In our research, we have utilized high energy ultrasound for the liquefaction of different lignocellulosic materials, wood wastes in particular. We developed a highly efficient way of transforming this biomass waste into valuable chemicals. It was found, that the reaction yield in all experiments was high and that the reaction times were shortened up to nine times when using the ultrasound process with smaller residual particles and with no influence on the hydroxyl number of the final products. The use of the ultrasound process inhibits the formation of the large molecular structures during the liquefaction from the degradation products, by keeping the reactive segments apart and due to such a short reaction time being used. The short reaction time and subsequent low energy consumption for the liquefaction reaction leads to the creation of the new method for the transformation of the wood waste materials into valuable chemicals.     

Comparison of ultrasound and skinfold measurements in assessment of subcutaneous and total fatness

Ultrasound (A-scan mode) and skinfold methods were evaluated in the measurement of subcutaneous fat thickness and prediction of total fat weight (by whole body potassium counting). Based on intraobserver correlations on 39 men at 15 body sites, skinfold caliper measurements were more reproducible than ones obtained by ultrasound. Measurements made with the two techniques at the same site typically produced different mean estimates of fat thickness. However, scores were often highly correlated with each other, indicating similar relative rankings of subjects by each technique. Skinfolds were more highly correlated with total fat weight than were ultrasound measurements, but body weight and anthropometric measures had even higher correlations with total fat weight. Anthropometric measurements were highly correlated with fatness because of their association with body weight, and when this relationship was statistically controlled for, they typically lost their predictive effectiveness. Multiple regression analyses revealed that the best predictors of fat weight were body weight along with skinfold and ultrasound measurements. These results suggest that skinfolds are a more effective means of assessing subcutaneous fat than ultrasound, especially when the large difference in cost of equipment is considered.     

Ultrasound, microbubbles and the blood-brain barrier

The blood–brain barrier (BBB) is a specialized system of capillary endothelial cells that protects the brain from harmful substances in the blood stream, while supplying the brain with the required nutrients for proper function. The BBB controls transport through both tight junctions and metabolic barriers and is often a rate-limiting factor in determining permeation of therapeutic drugs into the brain. It is a significant obstacle for delivery of both small molecules and macromolecular agents. Although many drugs could be potentially used to treat brain disease, there has been no method that allows non-invasive-targeted delivery through the BBB. Recently, promising studies indicate that ultrasound can be used to locally deliver a drug or gene to a specific region of interest in the brain. If microbubbles are combined with ultrasound exposure, the effects of ultrasound can be focused upon the vasculature to reduce the acoustic intensity needed to produce BBB opening. Several avenues of transcapillary passage after ultrasound sonication have been identified including transcytosis, passage through endothelial cell cytoplasmic openings, opening of tight junctions and free passage through injured endothelium. This article reviews the topic of transient disruption of the BBB with ultrasound and microbubbles and addresses related safety issues. It also discusses possible roles of the BBB in brain disease and potential interactions with ultrasound and microbubbles in such disease states.     

Dissecting the role of polarity regulators in cancer through the use of mouse models

Loss of cell polarity and tissue architecture is a hallmark of aggressive epithelial cancers. In addition to serving as an initial barrier to tumorigenesis, evidence in the literature has pointed towards a highly conserved role for many polarity regulators during tumor formation and progression. Here, we review recent developments in the field that have been driven by genetically engineered mouse models that establish the tumor suppressive and context dependent oncogenic function of cell polarity regulators in vivo. These studies emphasize the complexity of the polarity network during cancer formation and progression, and reveal the need to interpret polarity protein function in a cell-type and tissue specific manner. They also highlight how aberrant polarity signaling could provide a novel route for therapeutic intervention to improve our management of malignancies in the clinic.     

Ultrasound-mediated delivery of echogenic immunoliposomes to porcine vascular smooth muscle cells in vivo

Vascular smooth muscle cells (VSMCs) are important targets in the treatment of atherosclerosis. However, the arterial media, where the majority of VSMCs reside, have proven to be a difficult target for drug/gene delivery. We have demonstrated that ultrasound enhances drug/gene delivery to VSMCs in vitro by using echogenic immunoliposomes (ELIPs) as the vector. This study aimed to evaluate whether ultrasound can similarly enhance the delivery of an agent to VSMCs, particularly within the arterial media, in vivo, using ELIP. Anti–smooth-muscle cell actin-conjugated calcein-loaded ELIP were injected into the peripheral arteries of Yucatan miniswine (n?=?8 arterial pairs). The right-sided porcine arteries were treated with 1-MHz continuous-wave ultrasound at a peak-to-peak pressure amplitude of 0.23?±?0.05?MPa for 2 minutes. The contralateral arteries served as controls. Arteries were harvested after 30 minutes and imaged with fluorescence microscopy. Image data were converted to grayscale and analyzed by using computer-assisted videodensitometry. There was significant improvement in calcein uptake in all three arterial layers in the arteries exposed to ultrasound (>?300%). This enhanced uptake was site specific and appeared limited to the ultrasound-treated arterial segment. We have demonstrated enhanced delivery of a small molecule to VSMCs in all arterial wall layers, particularly the arterial media, using ultrasound and targeted ELIP. The combined effect of ultrasound exposure and ELIP as a contrast agent and a drug/gene-bearing vector has the potential for site-specific therapy directed at VSMC function.     

Can dolphins heal by ultrasound?

In recent years, dolphin-assisted therapy has become very popular and an increasing number of facilities offer therapy programs with dolphins worldwide. To this date, there are no studies concerning the behavior of dolphins during these therapies. As a result of speculations that the echolocation of dolphins may play an important role for the success of the therapy and the high publicity of this in the media, people pay much more for dolphin-assisted than for other animal-assisted therapy programs. Based on publications in medicine, we will show that ultrasound emitted by dolphins could have an effect on biological tissue under some circumstances; such as sufficient intensity, repeated application over several days or weeks and a certain application duration per session. We recorded 83 sessions at the “Dolphins Plus”, a fenced area with ocean water in the Florida Keys. Our observations demonstrate that only one out of five observed dolphins behave significantly differently towards patients compared to other humans and that the duration of the observed close contacts did not meet the requirements for common ultrasound therapies.     

基于超声的多模式功能化对比剂研究进展

超声对比剂的使用使得超声诊断更加准确,扩大了超声成像的应用范围。但单一影像技术难以满足肿瘤等重大疾病临床诊断和治疗的需求。因此开发以超声对比剂为核心,具有多模式成像功能,或同时兼备肿瘤诊断和治疗功能的多模式功能化对比剂是目前的一大研究热点。多模式成像的结合可以实现优势互补,诊断和治疗功能的结合为使得肿瘤等重大疾病的解决提供了新理念和新希望,具有重要意义。本文就基于超声的多模式功能化对比剂进行综述。     

An experimental study of the use of ultrasound to facilitate the loading of trehalose into platelets

Trehalose is widely used as a freeze-drying protectant in biomaterial preservation. For this purpose, trehalose has to be loaded into the cells but this is difficult and many methods have been tried. The application of ultrasound can temporarily permeabilize cell membranes, which offers a non-chemical, non-viral, and non-invasive method of cellular drug delivery. Ultrasound is employed here to enhance the loading of trehalose into human platelets. Two frequencies were used, 25 kHz and 800 kHz. The estimated intensity of ultrasound in the sample was varied from 0 to 1.5 W/cm². The trehalose concentration in the platelets was 11.27 ± 2.53 mmol/L when Wolkers et al.’s method was used without ultrasound. The application of 0.8 W/cm², 800 kHz ultrasound for 1 h increased the concentration of trehalose loaded by 54%. The application of 0.8 W/cm², 25 kHz ultrasound for 30 min increased the trehalose concentration that was loaded by 172%. The number and mean volume of the platelets following ultrasonic radiation in these two cases remained normal as compared with fresh untreated platelets. Morphological examination of the radiated platelets showed slight changes. Although further work is needed, ultrasound has been shown to be efficient for the loading of trehalose into platelets.     

Including surrounding tissue improves ultrasound-based 3D mechanical characterization of abdominal aortic aneurysms

ObjectivesIn this study the influence of surrounding tissues including the presence of the spine on wall stress analysis and mechanical characterization of abdominal aortic aneurysms using ultrasound imaging has been investigated.MethodsGeometries of 7 AAA patients and 11 healthy volunteers were acquired using 3-D ultrasound and converted to finite element based models. Model complexity of externally unsupported (aorta-only) models was complemented with inclusion of both soft tissue around the aorta and a spine support dorsal to the aorta. Computed 3-D motion of the aortic wall was verified by means of ultrasound speckle tracking. Resulting stress, strain, and estimated shear moduli were analyzed to quantify the effect of adding surrounding material supports.ResultsAn improved agreement was shown between the ultrasound measurements and the finite element tissue and spine models compared to the aorta-only models. Peak and 99-percentile Von Mises stress showed an overall decrease of 23–30%, while estimated shear modulus decreased with 12–20% after addition of the soft tissue. Shear strains in the aortic wall were higher in areas close to the spine compared to the anterior region.ConclusionsImproving model complexity with surrounding tissue and spine showed a homogenization of wall stresses, reduction in homogeneity of shear strain at the posterior side of the AAA, and a decrease in estimated aortic wall shear modulus. Future research will focus on the importance of a patient-specific spine geometry and location.     

Emerging technologies in therapeutic ultrasound: Thermal ablation to gene delivery

Ultrasound is used today in medicine as a modality for diagnostic imaging. Recently, there have been numerous reports on the application of thermal and nonthermal ultrasound energy for treating various diseases. In addition to thermal ablation of tumors, non-thermal ultrasound combined with drugs and genes have led to much excitement especially for cancer treatment, vascular diseases, and regenerative medicine. Ultrasound energy can enhance the effects of thrombolytic agents such as urokinase for treatment of stroke and acute myocardial infarction. New ultrasound technologies have resulted in advanced devices such as a) ultrasound catheters, b) Non-invasive methods as high intensity focused ultrasound (HIFU) in conjunction with MRI and CT is already being applied in the clinical field, c) Chemical activation of drugs by ultrasound energy for treatment of tumors is another new field recently termed "Sonodynamic Therapy", and d) Combination of genes and microbubble have induced great hopes for ideal gene therapy (sonoporation). Various examples of ultrasound combined modalities are under investigation which could lead to revolutionary therapy.