Ultrasound molecular imaging has been developed in the past two decades with the goal of non-invasively imaging disease phenotypes on a cellular level not depicted on anatomic imaging. Such techniques already play a role in pre-clinical research for the assessment of disease mechanisms and drug effects, and are thought to in the future contribute to earlier diagnosis of disease, assessment of therapeutic effects and patient-tailored therapy in the clinical field. In this review, we first describe the chemical composition and structure as well as the in vivo behavior of the ultrasound contrast agents that have been developed for molecular imaging. We then discuss the strategies that are used for targeting of contrast agents to specific cellular targets and protocols used for imaging. Next we describe pre-clinical data on imaging of thrombosis, atherosclerosis and microvascular inflammation and in oncology, including the pathophysiological principles underlying the selection of targets in each area. Where applicable, we also discuss efforts that are currently underway for translation of this technique into the clinical arena.

Objective: Contrast-enhanced ultrasound molecular imaging (CEUMI) of endothelial expression of VCAM (vascular cell adhesion molecule)-1 could improve risk stratification for atherosclerosis. The microbubble contrast agents developed for preclinical studies are not suitable for clinical translation. Our aim was to characterize and validate a microbubble contrast agent using a clinically translatable single-variable domain immunoglobulin (nanobody) ligand. Approach and Results: Microbubble with a nanobody targeting VCAM-1 (MB cAbVcam1-5 ) and microbubble with a control nanobody (MB VHH2E7 ) were prepared and characterized in vitro. Attachment efficiency to VCAM-1 under continuous and pulsatile flow was investigated using activated murine endothelial cells. In vivo CEUMI of the aorta was performed in atherosclerotic double knockout and wild-type mice after injection of MB cAbVcam1-5 and MB VHH2E7 . Ex vivo CEUMI of human endarterectomy specimens was performed in a closed-loop circulation model. The surface density of the nanobody ligand was 3.5×10 5 per microbubble. Compared with MB VHH2E7 , MB cAbVcam1-5 showed increased attachment under continuous flow with increasing shear stress of 1-8 dynes/cm 2 while under pulsatile flow attachment occurred at higher shear stress. CEUMI in double knockout mice showed signal enhancement for MB cAbVcam1-5 in early ( P =0.0003 versus MB VHH2E7 ) and late atherosclerosis ( P =0.007 versus MB VHH2E7 ); in wild-type mice, there were no differences between MB cAbVcam1-5 and MB VHH2E7 . CEUMI in human endarterectomy specimens showed a 100% increase in signal for MB cAbVcam1-5 versus MB VHH2E7 (20.6±27.7 versus 9.6±14.7, P =0.0156). Conclusions: CEUMI of the expression of VCAM-1 is feasible in murine models of atherosclerosis and on human tissue using a clinically translatable microbubble bearing a VCAM-1 targeted nanobody.

The analysis of the quality of medical care for the rural population has been taken in the «Ustinskaya Regional Hospital» of the Kalmyk Republic (further on referenced as «URH»). Analysis goal. To investigate the basic principles of medical care for the rural population and determine the major open issues regarding healthcare, considering URH as an example. Assessment methods. Two examination phases have been conducted: 1. Assessment of disease structure, equipment level, and overall work efficiency of URH 2. Analysis of the voluntary patient survey The investigation covered 653 respondents of both genders, aged between 20 and 70 with an average of 47,5 years [23,2; 68,1] Results - the principles of medical care at Ustinsky Region of Kalmyk Republic has been considered as satisfactory. The whole population of the Ustinsky Region makes 9958 people (including 8178 adults and 1780 kids). The population is divided into 3 therapeutic and 2 pediatric departments, according to the actual standards. From the nosology perspective, regional clinical examination covers 95.3% of the respiratory system diseases and 91% of cardiovascular system pathologies. In 2016 more than 95% of the survey respondents mentioned positive changes in the treatment level of URH. Own health level was considered as “good” by 96% of respondents. About 16% of patients were listed in the dispensary, but only 75% of them were screened annually. The complications with receiving preferential medicines were experienced by 46% of patients. The commute to the regional hospital takes 30 minutes for 58% of respondents, and over 60 minutes for 18% of them. Medical staff, conducting prophylactic measures has been spotted by 49% of respondents. Discussion. Dispensary observation has been properly focused on prophylaxis only in 2016. Conclusions. The overall level of medical care for the rural population of the assessed regional center has been considered as satisfactory.

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