A responsive MRI contrast agent to monitor functional cell status

It has been shown that insoluble Gd chelates are suitable MRI contrast agents for conditional activation by intracellular lipases. The DTPA-based, insoluble, inactive contrast agent was internalized into dendritic cells by phagocytosis. Cleavage of long aliphatic side chains by intracellular lipase activity leads to the contrast agents solubility and hereby its activation depending on the enzyme expression. Uptake and activation of the contrast agent was much reduced in Flt3+ CD11b+ progenitor cells. Detectability limits in the T(1)-weighted MR images were estimated in phantoms and in vivo in the rat brain. Marginal toxic effects were only observed at very high concentrations of the contrast agent. The chelate can easily be modified to be targeted by enzymes expressed during specific change of cell status like activation or differentiation. Such a system is suitable for functional cellular in vivo MR imaging.     

Confounding effects of myocardial background intensity and attenuation in contrast echocardiography: an in vivo study

It has been shown in vitro that the time-intensity data of echo contrast agents may be influenced by the background intensity of the myocardium and attenuation at high contrast agent concentrations. In the present study, these effects are evaluated from in vivo data. An effect of background intensity of the myocardium on the determination of the transit rate of the contrast agent could not be demonstrated unambiguously. A statistically significant relation between transit rate and background intensity was found only for intermediate flows in the transmural region. The magnitude of this relation was such that it does not provide a serious source of error. Attenuation and shadowing typically underestimate the transit rate of the contrast agent, which results in overestimation of flow. It is recommended that the lowest doses of contrast agent inducing myocardial opacification should be applied.     

Feasibility study of time-intensity-based blood flow measurements using deconvolution.

Ultrasonic contrast agents have been used to enhance the acoustic backscattered intensity of blood and to assist the assessment of blood flow parameters. One example is the time-intensity method based on the indicator-dilution theory. In this case, a mixing chamber model can be employed to describe the concentration of the contrast agent as a function of time. By measuring the time intensities at both the input and output of the blood mixing chamber, blood flow information can be obtained if proper deconvolution techniques are applied. Note that most deconvolution techniques assume a linear and time invariant (LTI) system for the mixing of the contrast agent with blood. In this paper, the hypothesis that a blood mixing chamber is an LTI system was tested. Several aspects were studied. One aspect was the linear relationship between the concentration of the contrast agent and the backscattered intensity. The other aspect was the dependence of the derived time constants on the concentration. The concept of an effective mixing volume was also introduced and evaluated. Finally, the input and the output time constants were measured and compared to theory under the LTI assumption. Extensive experiments were performed. Two in vitro flow models were constructed and two contrast agents were used. Results indicated that the LTI assumption does not hold and quantitative flow estimation is generally not possible. Nonetheless, the indicator-dilution theory can still be applied if only relative measurements of the flow rate are required.     

Mathematical modeling of the dilution curves for ultrasonographic contrast agents

Most techniques using sonographic contrast agents are based on introducing the agent intravenously. The sonographic changes occur over time and follow a characteristic "skewed gaussian curve," often referred to as the indicator dilution curve. This study uses principles of linear acoustics and tracer kinetics to develop a quantitative model for the indicator dilution curve. A rapid increase in image brightness occurs after bolus injection; brightness peaks after a time related to the blood flow and stability of the contrast agent, which is followed by an asymptotic decrease in image brightness. The net image enhancement, represented by the area under the dilution curve, increases nonlinearly with the injected dose. In stable contrast agents the peak-time and mean transit time are related directly to the flow rate. This relationship changes when the microbubbles of a contrast agent collapse. In an unstable contrast agent the indicator dilution curve is attenuated and peaks earlier than expected on the basis of flow rate. The extent of shift in the mean transit time varies with the half-life of the contrast agent and follows a sigmoid relationship. In conclusion, the properties of the time-videointensity (indicator dilution) curves are significantly affected by the attenuation and stability of the contrast agents. These factors must be taken into consideration in deriving flow related information.     

Enzyme‐responsive PARACEST MRI contrast agents: a new biomedical imaging approach for studies of the proteasome

Proteases are important biomarkers for many biological processes and are popular targets for therapeutics investigations. A protease can be detected by monitoring changes in the paramagnetic chemical exchange saturation transfer (PARACEST) effect of a MRI contrast agent that serves as a substrate for the protease. To translate this type of responsive PARACEST MRI contrast agent to in vivo applications, the sensitivity, timing, specificity and validation of the response of the agent must be evaluated. This report demonstrates that PARACEST MRI contrast agents can be used to detect nanomolar concentrations of proteases, can be designed to preferentially detect the protease caspase‐3 relative to caspase‐8, and can be detected within the 15 min time frame of typical MRI studies. The response can be validated using an unresponsive PARACEST MRI contrast agent as a control. A survey of the MEROPS database shows that this approach may also be applied to detect other proteases, and therefore may represent a new platform technology for studies of the proteasome. Copyright © 2007 John Wiley & Sons, Ltd.     

亚微米级超声微泡造影剂的制备及体外基因转染效率的实验研究

目的 探索制备亚微米级超声微泡造影剂的方法 ,以GFP作为目的 基因验证其作为一种新型基因载体的可行性.方法 以高剪切分散法制备超声微泡造影剂,透射电镜及激光粒度分析仪检测其形态及粒径;将超声微泡造影剂与不同剂量的绿色荧光蛋白质粒PShuttle-IRES-hrGFP-1结合后转染HepG2细胞,利用荧光显微镜观察并检测其基因转染效率.结果 自制超声微泡造影剂为均匀分散的圆泡,粒径分布在282.2～415.7 nm之间,平均值为(335±5)nm,达到亚微米级;该微泡能将GFP基因成功转运到HepG2细胞内并高效表达,转染效率达32.61%±3.42%.结论 自制亚微米级超声微泡造影剂粒径小、分散均匀,并能成功转运外源DNA进入细胞内,可作为一种新型基因载体.     

高分子材料超声对比剂的制备及显影特征

背景：目前所用的超声对比剂均为内含不同气体成分的微气泡,其外壳材料多数为表面活性剂类、人血蛋白质类、脂类等。随着高分子化学的发展,高分子材料对比剂成为超声对比剂研究领域的热点。目的：探讨各种超声对比剂制备中遇到的困难以及解决方法,从而最终寻找合理的高分子材料超声对比剂。方法：采用电子检索的方式,在万方数据库（http：//www.wanfangdata.com.cn/）中检索2005-01/2010-12有关高分子材料应用于超声造影方面的研究文章,关键词为＂高分子材料,超声,对比剂＂。排除重复研究、普通综述或Meta分析类文章,筛选纳入26篇文献进行评价。结果与结论：近年来随着高分子科学与多学科融合的分子医学的兴起和快速发展,显像对比剂受到了越来越广泛的关注。高分子材料超声对比剂由于具有好的生物相容性,粒径大小均匀,良好的抗压性能,较长的显影持续时间等特点,已成为目前研究的热点。其中靶向微泡对比剂经静脉注射可到达特定靶区,低功率超声作用下可提高局部组织显影的分辨率。携带治疗药物或基因的靶向微泡对比剂在低频（1MHz）超声作用下可以产生瞬态空化效应,迫使细胞膜的通透性增加,从而有效提高了药物或基因的转染率。如今,靶向微泡携抗肿瘤药物联合超声作用正逐渐成为治疗肿瘤的一种新模式,是近期医学研究的一个热点。超声联合靶向微泡技术在临床诊断和治疗中显示出了较大的优势,但其准确的生物学机制目前医学界还未清楚,超声治疗参数需进一步优化。     

高分子材料超声对比剂的制备及显影特征

背景:目前所用的超声对比剂均为内含不同气体成分的微气泡,其外壳材料多数为表面活性剂类、人血蛋白质类、脂类等。随着高分子化学的发展,高分子材料对比剂成为超声对比剂研究领域的热点。目的:探讨各种超声对比剂制备中遇到的困难以及解决方法,从而最终寻找合理的高分子材料超声对比剂。方法:采用电子检索的方式,在万方数据库(http://www.wanfangdata.com.cn/)中检索2005-01/2010-12有关高分子材料应用于超声造影方面的研究文章,关键词为"高分子材料,超声,对比剂"。排除重复研究、普通综述或Meta分析类文章,筛选纳入26篇文献进行评价。结果与结论:近年来随着高分子科学与多学科融合的分子医学的兴起和快速发展,显像对比剂受到了越来越广泛的关注。高分子材料超声对比剂由于具有好的生物相容性,粒径大小均匀,良好的抗压性能,较长的显影持续时间等特点,已成为目前研究的热点。其中靶向微泡对比剂经静脉注射可到达特定靶区,低功率超声作用下可提高局部组织显影的分辨率。携带治疗药物或基因的靶向微泡对比剂在低频(1MHz)超声作用下可以产生瞬态空化效应,迫使细胞膜的通透性增加,从而有效提高了药物或基因的转染率。如今,靶向微泡携抗肿瘤药物联合超声作用正逐渐成为治疗肿瘤的一种新模式,是近期医学研究的一个热点。超声联合靶向微泡技术在临床诊断和治疗中显示出了较大的优势,但其准确的生物学机制目前医学界还未清楚,超声治疗参数需进一步优化。     

Applicability of biomass autohydrolyzates as corrosion inhibiting deicing agents

A deicing agent from renewable resources is necessary to overcome the disadvantages of traditional deicing agents. In this study, biomass autohydrolyzate was evaluated for its applicability as corrosion inhibiting deicing agents. Autohydrolyzates treated with alkali showed significant freezing point depression and corrosion inhibiting effects on mild steel. Freezing points for autohydrolyzate treated with 2% (w/w) sodium hydroxide were depressed at −64.0 °C (56% solids content), and its maximum corrosion inhibiting efficiency was 61.5%. This material was found to be more effective than a tested commercial deicing agent. This strong performance is considered due to the xylooligosaccharides being degraded to various sugar acid compounds under alkaline treatment conditions, providing the mixture with solutes with corrosion inhibition potency. In conclusion, alkaline treated autohydrolyzate could replace traditional deicing agents based on superior performance and a sustainable production scheme.

A deicing agent from renewable resources is necessary to overcome the disadvantages of traditional deicing agents. Biomass autohydrolyzates have a potential as corrosion inhibiting deicing agent.     

Updated treatment for influenza A and B

Influenza causes significant morbidity and mortality and is responsible for considerable medical expenditures. Vaccination is the most effective public health measure to combat this illness. Amantadine and rimantadine are older antiviral agents that have been important adjuncts in the prevention and treatment of influenza A outbreaks. Zanamivir and oseltamivir are newer agents indicated for the treatment of both influenza A and B. For antiviral agents to be effective, they must be used within 48 hours of the onset of influenza symptoms. Antiviral agents reduce the duration of fever and illness by one to two and one-half days and also reduce the severity of some symptoms. Use of amantadine or rimantadine is appropriate if influenza virus A is known to be the predominant agent in a particular year or location. Data need to be evaluated on the development of resistance and use of the newer antiviral agents in geriatric patients, high-risk patients and children. For optimal use of antiviral agents, patients with influenza symptoms must present early, and family physicians must accurately and rapidly diagnose the illness.     

Acoustic radiation force in vivo: a mechanism to assist targeting of microbubbles

The goal of targeted imaging is to produce an enhanced view of physiological processes or pathological tissue components. Contrast agents may improve the specificity of imaging modalities through selective targeting, and this may be particularly significant when using ultrasound (US) to image inflammatory processes or thrombi. One means of selective targeting involves the attachment of contrast agents to the desired site with the use of a specific binding mechanism. Because molecular binding mechanisms are effective over distances on the order of nanometers, targeting effectiveness would be greatly increased if the agent is initially concentrated in a particular region, and if the velocity of the agent is decreased as it passes the potential binding site. Ultrasonic transmission produces a primary radiation force that can manipulate microbubbles with each acoustic pulse. Observations demonstrate that primary radiation force can displace US contrast agents from the center of the streamline to the wall of a 200-microm cellulose vessel in vitro. Here, the effects of radiation force on contrast agents in vivo are presented for the first time. Experimental results demonstrate that radiation force can displace a contrast agent to the wall of a 50-microm blood vessel in the mouse cremaster muscle, can significantly reduce the velocity of flowing contrast agents, and can produce a reversible aggregation. Acoustic radiation force presents a means to localize and concentrate contrast agents near a vessel wall, which may assist the delivery of targeted agents.     

小鼠视网膜母细胞瘤的靶向超声造影成像研究

目的评估携带单纯疱疹病毒Ⅰ型胸苷激酶（HSV1-tk）质粒和血管内皮细胞生长因子受体2（VEGFR2）抗体的靶向超声造影剂Targesphere SA对视网膜母细胞瘤的造影效果。方法建立小鼠眼视网膜母细胞瘤模型,选取10例明显突出眼表的肿瘤,直径〉5 mm时行超声造影检查。制备携带HSV1-tk质粒和VEGFR2抗体的靶向微泡Targesphere SA。超声造影采用Sequoia 512型彩色多普勒超声诊断仪。先行声诺维超声造影,眼球后注射约50μl,同步录像并计时,观察至造影剂完全消退。15 min后,采用与前者同样的方法进行靶向造影剂成像。回放录像,由3名有经验的超声医师比较2种造影剂对肿瘤的增强时间、达峰时间、达峰强度及消退特征。结果 2种造影剂注入后,肿瘤内部均很快（1~2 s）可见有造影剂进入,声诺维组6~9 s增强达高峰,靶向造影剂组5~9 s增强达高峰,2种造影剂对肿瘤的增强程度一致,均呈高增强。60 s后声诺维组造影剂明显消退,而靶向造影剂组仍呈高增强。2 min后声诺维组肿瘤内的造影剂明显消退,而靶向造影剂组仍呈高增强。5 min后声诺维组肿瘤内造影剂完全消退,而靶向造影剂组仍呈高增强。10 min后靶向造影剂组肿瘤内呈高增强,15 min后造影剂明显消退。结论靶向造影剂能对视网膜母细胞瘤进行有效的超声造影成像,与声诺维比较,在2 min内无明显差异,2 min后增强效果更好,持续时间更长。     

The Delayed Onset of Subharmonic and Ultraharmonic Emissions from a Phospholipid-Shelled Microbubble Contrast Agent

Characterizing the non-linear response of microbubble contrast agents is important for their efficacious use in imaging and therapy. In this article, we report that the subharmonic and ultraharmonic response of lipid-shelled microbubble contrast agents exhibits a strong temporal dependence. We characterized non-linear emissions from Targestar-p microbubbles (Targeson Inc., San Diego, CA, USA) periodically for 60 min, at 10 MHz excitation frequency. The results revealed a considerable increase in the subharmonic and ultraharmonic response (nearly 12–15 and 5–8 dB) after 5–10 min of agent preparation. However, the fundamental and the harmonic response remained almost unchanged in this period. During the next 50 min, the subharmonic, fundamental, ultraharmonic, and harmonic responses decreased steadily by 2–5 dB. The temporal changes in the non-linear behavior of the agent appeared to be primarily mediated by gas-exchange through the microbubble shell; temperature and prior acoustic excitation based mechanisms were ruled out. Further, there was no measurable change in the agent size distribution by static diffusion. We envisage that these findings will help obtain reproducible measurements from agent characterization, non-linear imaging, and fluid-pressure sensing. These findings also suggest the possibility for improving non-linear imaging by careful design of ultrasound contrast agents.     

Magnetic resonance imaging of the pediatric abdomen.

In many ways, MRI of the pediatric abdomen is in its infancy. Motion will be a problem with most of the current pulse sequences, but the problem appears manageable given many of the newer software options for motion suppression. Faster pulse sequences (approaching CT scan times) will serve to improve image quality and reduce the need for sedation. Identification of a reliable enteric contrast agent probably will expand the current utility of MRI beyond evaluation of solid abdominal viscera. Although preliminary results appear promising, controlled comparative studies are necessary to determine the exact role of MRI in diagnosis and staging of common pediatric abdominal malignancies. The addition of MRI intravenous contrast agents and MR spectroscopy are anticipated to add depth and specificity to the diagnostic potential of this exciting modality.     

Quantification of microbubble destruction of three fluorocarbon-filled ultrasonic contrast agents

The assessment of myocardial blood velocity using ultrasonic contrast agents is based on the premise that the vast majority of contrast microbubbles within a myocardial region can be destroyed by an acoustic pulse of sufficient magnitude. Determination of the period of time after destruction that a region of myocardium needs to reperfuse may be used to assess myocardial blood velocity. In this study, we investigated the acoustic pressure sensitivity of three solutions of intravenous fluorocarbon-filled contrast agents and the magnitude of acoustic pulse required to destroy the contrast agent microbubbles. A novel tissue-mimicking phantom was designed and manufactured to investigate the relationships between mean integrated backscatter, incident acoustic pressure and number of frames of insonation for three fluorocarbon-filled contrast agents (Definity(R), Optison(R), and Sonazoid(R), formerly NC100100). Using a routine clinical ultrasound (US) scanner (Acuson XP-10), modified to allow access to the unprocessed US data, the contrast agents were scanned at the four acoustic output powers. All three agents initially demonstrated a linear relationship between mean integrated backscatter and number of frames of insonation. For all three agents, mean integrated backscatter decreased more rapidly at higher acoustic pressures, suggesting a more rapid destruction of the microbubbles. In spite of the fact that there was no movement of microbubbles into or out of the beam, only the results from Definity(R) suggested that a complete destruction of the contrast agent microbubbles had occurred within the total duration of insonation in this study.     

Multimodal liposomes for SPECT/MR imaging as a tool for in situ relaxivity measurements

One of the major challenges of MR imaging is the quantification of local concentrations of contrast agents. Cellular uptake strongly influences different parameters such as the water exchange rate and the pool of water protons, and results in alteration of the contrast agent's relaxivity, therefore making it difficult to determine contrast agent concentrations based on the MR signal only. Here, we propose a multimodal radiolabeled paramagnetic liposomal contrast agent that allows simultaneous imaging with SPECT and MRI. As SPECT‐based quantification allows determination of the gadolinium concentration, the MRI signal can be deconvoluted to get an understanding of the cellular location of the contrast agent. The cell experiments indicated a reduction of the relaxivity from 2.7 ± 0.1 m m ^?1 s^?1 to a net relaxivity of 1.7 ± 0.3 m m ^?1 s^?1 upon cellular uptake for RGD targeted liposomes by means of the contrast agent concentration as determined by SPECT. This is not observed for nontargeted liposomes that serve as controls. We show that receptor targeted liposomes in comparison to nontargeted liposomes are taken up into cells faster and into subcellular structures of different sizes. We suggest that the presented multimodal contrast agent provides a functional readout of its response to the biological environment and is furthermore applicable in in vivo measurements. As this approach can be extended to several MRI‐based contrast mechanisms, we foresee a broader use of multimodal SPECT/MRI nanoparticles to serve as in vivo sensors in biological or medical research. Copyright © 2011 John Wiley & Sons, Ltd.     

A spatially-distributed computational model to quantify behaviour of contrast agents in MR perfusion imaging

Contrast agent enhanced magnetic resonance (MR) perfusion imaging provides an early, non-invasive indication of defects in the coronary circulation. However, the large variation of contrast agent properties, physiological state and imaging protocols means that optimisation of image acquisition is difficult to achieve. This situation motivates the development of a computational framework that, in turn, enables the efficient mapping of this parameter space to provide valuable information for optimisation of perfusion imaging in the clinical context. For this purpose a single-compartment porous medium model of capillary blood flow is developed which is coupled with a scalar transport model, to characterise the behaviour of both blood-pool and freely-diffusive contrast agents characterised by their ability to diffuse through the capillary wall into the extra-cellular space. A parameter space study is performed on the nondimensionalised equations using a 2D model for both healthy and diseased myocardium, examining the sensitivity of system behaviour to Peclet number, Damköhler number (Da), diffusivity ratio and fluid porosity. Assuming a linear MR signal response model, sample concentration time series data are calculated, and the sensitivity of clinically-relevant properties of these signals to the model parameters is quantified. Both upslope and peak values display significant non-monotonic behaviour with regard to the Damköhler number, with these properties showing a high degree of sensitivity in the parameter range relevant to contrast agents currently in use. However, the results suggest that signal upslope is the more robust and discerning metric for perfusion quantification, in particular for correlating with perfusion defect size. Finally, the results were examined in the context of nonlinear signal response, flow quantification via Fermi deconvolution and perfusion reserve index, which demonstrated that there is no single best set of contrast agent parameters, instead the contrast agents should be tailored to the specific imaging protocol and post-processing method to be used.     

Comparison of thrombolytic agents: mechanisms of action

The new generation of plasminogen activators promises certain advantages over the first-generation agents, particularly enhanced clot specificity. The tissue distribution, half-life, therapeutic profile, and optimum dosage, however, need to be evaluated for each chemically different agent. Whatever advantages these third-generation agents offer over the existing natural prototypes of the plasminogen activators will not be determined for some time. In addition, because an "agent of choice" has not been identified at this time, critical care nurses must understand the mechanisms of action of the various thrombolytic agents to ensure accurate and appropriate assessment, problem identification, and intervention in this era of reperfusion with thrombolytic therapy.     

MR contrast agents in hepatic cirrhosis and chronic hepatitis.

Chronic liver disease alters the gross architecture of the liver and its arterial and portal blood supply. The relative proportion of regenerative hepatocytes, necrosis, extracellular interstitial space, and fibrosis is responsible for liver enhancement after the administration of a contrast agent. Because contrast agents can be directed toward either the extracellular or the intracellular spaces, knowledge of the different parenchymal enhancement alterations seen after the administration of these agents is necessary to understand how chronic liver disease pathologic changes influence contrast-enhanced magnetic resonance (MR) images. This article reviews the effect of chronic liver disease on MR contrast enhancement, as well as the effect of altered enhancement on lesion detection and characterization. Both extracellular and intracellular contrast agents are considered.