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[Figure: see text].

In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of Alzheimer's disease. ADx-001 was tested at 0.10, 0.15, and 0.20 mmol Gd/kg. Gold standard post-mortem amyloid immunostaining was used for the determination of sensitivity and specificity. ADx-001 toxicity was evaluated in rats and monkeys at doses up to 0.30 mmol Gd/kg. ADx-001 pharmacokinetics were determined in monkeys and its tissue distribution was evaluated in rats. ADx-001-enhanced MRI demonstrated significantly higher (p < 0.05) brain signal enhancement in transgenic mice relative to wild type mice at all dose levels. ADx-001 demonstrated high sensitivity at 0.20 and 0.15 mmol Gd/kg and excellent specificity at all dose levels for in vivo imaging of β amyloid plaques. ADx-001 was well tolerated in rats and monkeys and exhibited the slow clearance from circulation and tissue biodistribution typical of PEGylated nanoparticles.

Non-invasive methods for estimating placental fractional blood volume (FBV) are of great interest for characterization of vascular perfusion in placentae during pregnancy to identify placental insufficiency that may be indicative of local ischemia or fetal growth restriction (FGR). Nanoparticle contrast-enhanced magnetic resonance imaging (CE-MRI) may enable direct placental FBV estimation and may provide a reliable, 3D alternative to assess maternal-side placental perfusion. In this pre-clinical study, we investigated if placental FBV at 14, 16, and 18 days of gestation could be estimated through contrast-enhanced MRI using a long circulating blood-pool liposomal gadolinium contrast agent that does not penetrate the placental barrier. Placental FBV estimates of 0.47 ± 0.06 (E14.5), 0.50 ± 0.04 (E16.5), and 0.52 ± 0.04 (E18.5) were found through fitting pre-contrast and post-contrast T1 values in placental tissue using a variable flip angle method. MRI-derived placental FBV was validated against nanoparticle contrast-enhanced computed tomography (CE-CT) derived placental FBV, where signal is directly proportional to the concentration of iodine contrast agent. The results demonstrate successful estimation of the placental FBV, with values statistically indistinguishable from the CT derived values.

Introduction: Visualization of the retroplacental clear space (RPCS) may provide critical insight into the development of abnormally invasive placenta (AIP). In this pre-clinical study, we characterized the appearance of the RPCS on magnetic resonance imaging (MRI) during the second half of gestation using a liposomal gadolinium contrast agent (liposomal-Gd)., Materials and Methods: Studies were performed in fifteen pregnant C57BL/6 mice at 10, 12, 14, 16, and 18 days of gestation. MRI was performed on a 1T permanent magnet scanner. Pre-contrast and post-contrast images were acquired using T1-weighted gradient-recalled echo (T1w-GRE) and T2-weighted fast spin echo (T2w-FSE) sequences. Animals were euthanized after imaging and feto-placental units harvested for histological examination. Visualization of the RPCS was scored by a maternal-fetal radiologist and quantified by measuring the contrast-to-noise ratio (CNR) on T1w images. Feto-placental features were segmented for analysis of volumetric changes during gestation., Results: Contrast-enhanced T1w images enabled the visualization of structural changes in placental development between days 10-18 of gestation. Although the placental margin on the fetal side was clearly visible at all time points, the RPCS was partially visible at day 10 of gestation, and clearly visible by day 12. Hematoxylin and eosin (H&E) staining of the placental tissue corroborated MRI findings of structural and morphological changes in the placenta., Conclusions: Contrast-enhanced MR imaging using liposomal-Gd enabled adequate visualization of the retroplacental clear space starting at day 12 of gestation. The agent also enabled characterization of placental structure and morphological changes through gestation., (Copyright © 2019. Published by Elsevier Ltd.)

Inflammation drives the degradation of atherosclerotic plaque, yet there are no non-invasive techniques available for imaging overall inflammation in atherosclerotic plaques, especially in the coronary arteries. To address this, we have developed a clinically relevant system to image overall inflammatory cell burden in plaque. Here, we describe a targeted contrast agent (THI0567-targeted liposomal-Gd) that is suitable for magnetic resonance (MR) imaging and binds with high affinity and selectivity to the integrin α4β1(very late antigen-4, VLA-4), a key integrin involved in recruiting inflammatory cells to atherosclerotic plaques. This liposomal contrast agent has a high T1 relaxivity (~2 × 10 5  mM -1 s -1 on a particle basis) resulting in the ability to image liposomes at a clinically relevant MR field strength. We were able to visualize atherosclerotic plaques in various regions of the aorta in atherosclerosis-prone ApoE -/- mice on a 1 Tesla small animal MRI scanner. These enhanced signals corresponded to the accumulation of monocyte/macrophages in the subendothelial layer of atherosclerotic plaques in vivo, whereas non-targeted liposomal nanoparticles did not demonstrate comparable signal enhancement. An inflammatory cell-targeted method that has the specificity and sensitivity to measure the inflammatory burden of a plaque could be used to noninvasively identify patients at risk of an acute ischemic event.

In a rat model of right free wall replacement, the transplantation of an engineered multilayered myocardial patch fabricated from a polycaprolactone membrane supporting a chitosan/heart matrix hydrogel induces significant muscular and vascular remodeling and results in a significantly higher right ventricular ejection fraction compared to use of a commercially available pericardium patch., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: A declining amplitude of body temperature circadian rhythm (BTCR) predicts decompensation or death in cardiomyopathic hamsters. We tested the hypothesis that changes in BTCR amplitude accompany significant changes in left ventricular (LV) size and function., Methods and Results: Using intraperitoneal transmitters, we continuously monitored the temperature of 30 male BIO TO-2 Syrian dilated cardiomyopathic hamsters. Cosinor analysis was used to detect significant changes--defined as changes >1 standard deviation from the baseline amplitude for 3 consecutive days--in BTCR amplitude over each hamster's lifespan. The Student t-test was used to compare BTCR variability and LV size and function (as assessed by 2D echocardiography) between baseline and the time that BTCR amplitude declined. All hamsters received 10 mg/kg furosemide daily. At the time of BTCR amplitude decline, functional parameters had changed significantly (P < .0001) from baseline: ejection fraction (0.31 ± 0.09% vs. 0.52 ± 0.08%), LV end-systolic volume (0.11 ± 0.03 vs. 0.05 ± 0.02 cm(3)), and LV end-diastolic volume (0.16 ± 0.04 vs. 0.10 ± 0.03 cm(3))., Conclusions: In decompensated cardiomyopathic hamsters, a decline in BTCR amplitude was associated with progression of heart failure and cardiac decompensation. Variation in BTCR warrants further investigation because of its potential implications for the diagnosis and treatment of cardiovascular disorders., (Published by Elsevier Inc.)

Background: Low body temperature is an independent predictor of poor prognosis in patients with congestive heart failure. The cardiomyopathic hamster develops progressive biventricular dysfunction, resulting in heart failure death at 9 months to 1 year of life. Our goal was to use cardiomyopathic hamsters to examine the relationship between body temperature and heart failure decompensation and death., Methods and Results: To this end, we implanted temperature and activity transducers with telemetry into the peritoneal space of 46 male Bio-TO-2 Syrian cardiomyopathic hamsters. Multiple techniques, including computing mean temperature, frequency domain analysis, and nonlinear analysis, were used to determine the most useful method for predicting poor prognosis. Data from 44 hamsters were included in our final analysis. We detected a decline in core body temperature in 98% of the hamsters 8+/-4 days before death (P < .001). We examined the dominant frequency of temperature variation (ie, the circadian rhythm) by using cosinor analysis, which revealed a significant decrease in the amplitude of the body temperature circadian rhythm 8 weeks before death (0.28 degrees C; 95% CI, 0.26-0.31) compared to baseline (0.36 degrees C; 95% CI, 0.34-0.39; P=.005). The decline in the circadian temperature variation preceded all other evidence of decompensation., Conclusions: We conclude that a decrease in the amplitude of the body temperature circadian rhythm precedes fatal decompensation in cardiomyopathic hamsters. Continuous temperature monitoring may be useful in predicting preclinical decompensation in patients with heart failure and in identifying opportunities for therapeutic intervention., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Congestive heart failure has long been one of the most serious medical conditions in the United States; in fact, in the United States alone, heart failure accounts for 6.5 million days of hospitalization each year. One important goal of heart-failure therapy is to inhibit the progression of congestive heart failure through pharmacologic and device-based therapies. Therefore, there have been efforts to develop device-based therapies aimed at improving cardiac reserve and optimizing pump function to meet metabolic requirements. The course of congestive heart failure is often worsened by other conditions, including new-onset arrhythmias, ischemia and infarction, valvulopathy, decompensation, end-organ damage, and therapeutic refractoriness, that have an impact on outcomes. The onset of such conditions is sometimes heralded by subtle pathophysiologic changes, and the timely identification of these changes may promote the use of preventive measures. Consequently, device-based methods could in the future have an important role in the timely identification of the subtle pathophysiologic changes associated with congestive heart failure.

Silent myocardial ischemia (SMI) is increasingly being recognized as part of the spectrum of ischemic heart disease. The spectrum of SMI ranges from asymptomatic coronary artery disease to critical illness necessitating intensive care. Although many diagnostic tools have been used to identify low- and high-risk subgroups, their use is limited by modest sensitivities and specificities. The present review identifies current concepts in the management of SMI in various clinical settings, as well as emerging technologies that may simplify the diagnosis and treatment of this condition.

The functional status of regional lymph drainage was studied in 40 rats with various models of pyoinflammatory abdominal diseases. It was shown that intratissue lymphopoiesis and lymph drainage were suppressed in general fecal peritonitis and hemorrhagic pancreonecrosis, which was evident in 1.59-3.15-fold elimination time of the lymphotropic indicator indigo carmine from the tissue and organ depot of the abdomen. The intravenous lymphostimulation with 10% rheomacrodex solution led to 1.06-1.51-fold increases in lymphopoiesis and lymph drainage. Regional intraaortic lymphogenic stimulation caused the most marked changes in the lymph circulatory bed, producing 1.22-1.56-fold effects on lymph drainage of abdominal organs and tissue.

The article deals with the results of experimental studies and clinical experience in the use of the plasma scalpel in 25 unbred dogs and 192 patients with diseases of the liver and gallbladder. Histological studies of the hepatic tissue after treatment with the laser scalpel allowed the conclusion that such manipulations are safe. The advantages of using the device for arresting bleeding and the flow of bile from the resected hepatic areas were revealed. The accumulated experience in operations on the liver and gallbladder with a plasma scalpel made it possible to develop optimal approaches to the use of the plasma flow in resections of the liver and to suggest three methods for removal of the gallbladder. Their introduction into practice improved the intraoperative possibilities of treatment of the gallbladder bed.

Intraarterial infusion of antibiotics provided a 1.39-2.84-fold regional increase in the antibiotic concentration as compared to that after the intravenous infusion in the organs and tissues of the abdominal cavity affected by an inflammatory process. Regional intraarterial lymphostimulation provided a 1.31-1.64-fold increase in the antibiotic resorption from the affected organs and tissues of the abdominal cavity to the relevant regional lymph nodes. Combined intraarterial administration of the antibiotic and lymphostimulant made it possible to provide high antibiotic concentrations in both the affected organs and tissues of the abdominal cavity and the respective portions of the regional lymphatic system.

The work is based on a comparison of data gained in experiments with the results of clinical examination of a large group of patients in the late-term period after endovascular occlusion of a patent ductus arteriosus (PDA). The regular features of the course of the morphological process in the zone of the PDA after implantation of a botallo-occluder into it were studied. Clinico-morphological parallels were made. The high efficacy and reliability of the new method of endovascular treatment of PDA, developed at the Moscow Second Medical institute, was substantiated morphologically and confirmed clinically.

The effect of magnetolaser irradiation on the liver in obstructive jaundice was studied in experiments on 500 rats. Magnetolaser irradiation was found to have a favourable effect on the functional morphology of the liver; it levels many morphological signs of hepatic insufficiency and thus provides the grounds for carrying out an operation on the bile ducts under optimal conditions. The suggested method of magnetolaser therapy was applied in 142 patients with hepatic insufficiency in obstructive jaundice. The study showed that magnetolaser therapy applied in complex treatment of hepatic insufficiency promotes active restoration of the function of the organ, significantly raises the efficacy of treatment, and reduces the term of the patient's hospital stay.

The resection of liver was undertaken in two series of experiments in rabbits with plasma and steel scalpels for comparison. After the interventions the haematological changes of stress nature were observed in animals. The changes of leucocytic and erythrocytic pictures and myelograms were more important and steady when the resections was made with plasma scalpel. The mentioned peculiarities must be taken into consideration in analysis of laboratory examinations in the clinic.

Five series of experiments were conducted on a model of hepatic insufficiency caused by obstructive jaundice to study the effect of semiconductor infrared laser in a range of 800-900 nm with a static magnetic field on some metabolic changes in the organism. Wistar rats weighing 200-250 g were used. The region of the liver was irradiated through an intact epilated skin. The results provide evidence that a definite role in the pathogenesis of hepatic insufficiency is played by intensification of LPO processes and diminution of antioxidant defence which leads, in turn, to reduction of the insulin-receptor interrelations and sharp decrease of hepatic cell metabolism.

Ion plasma light flux has been found to possess bacteriostatic effect in vitro and in vivo. Three-fold irradiation with ion plasma of a wound infected by a pathogenic Staphylococcus aureus strain reduced phase I of wound healing by three days and the overall time of healing by four-five days.

Experiments were conducted for comparative analysis of the use of elastic (Spandex) and nonelastic (Eticon) threads for the formation of anastomoses in vascular surgery. The results were studied in follow-up periods of up to 18 months. Thrombosis occurred at the site of anastomosis only in 6.8% of cases in which elastic threads were applied in contrast to 30% of cases in which nonelastic threads were used. Microscopy in the first case revealed neither marked inflammatory reaction nor necroses, which promoted regeneration and the formation of the neointima. In the second case, on the one hand, the nonelastic anastomosis between two elastic tubes creates conditions for thrombus formation, and on the other, the tension occurring periodically in this zone causes damage to the tissues and prevents rapid formation of the neointima.

The effect of ion plasma light flux on the genomes of auxotrophic Escherichia coli strain and Drosophilla melanogaster has been examined. Essentially no mutagenic effect was found in doses close to therapeutic ones.

The "Plasma scalpel CP-M" device was used in experiments on dogs to study the possibility of applying plasma irradiation in the surgery of the lungs. The morphology of their "plasma wound" and reparative processes was studied. The plasma device was employed in the clinic in 40 various operations on the lungs and thoracic wall for cleansing the pleural cavity and operative wound, hemostasis from the walls of the pleural cavity, and hermetic closure of the lung wound surface. It was established that the plasma scalpel can be used effectively in hermetic closure of defects in the pulmonary tissue and cleansing of the pleural cavity and operative wound; for arresting diffuse bleeding from the walls of the pleural cavity, the plasma scalpel may be used only in combination with other methods of hemostasis.

Lymphopoiesis stimulating drugs were injected into the blood of rabbits bearing Brown-Pearce transplantable tumor. It was found that treatment with mannitol targeted on osmoregulation mechanisms and terrilytin--on blood and lymph coagulation intensified the lymphogenic migration of tumor cells. When used in an experimental series involving endolymphic transplantation of tumor cells, the said drugs promoted tumor cell passage from lymph to blood, which resulted in an increased number of metastasis-bearing animals. It was also found that the promoting effect may be counteracted by preliminary endolymphic injection of a fat-soluble antitumor preparation. Lymphopoiesis and lymph flow stimulation in conjunction with thoracic duct draining may be used for removal of tumor cells from the lymphatics.

Functional properties of blood vessel prostheses to large degree depend on the longitudinal elasticity of their walls. Theoretical foundations for designing the physico-chemical properties of prostheses walls were worked out, and special methods and measuring apparatuses. New types of vascular textile prostheses make it possible to model biological tissues. The prostheses walls are a composition of polymers of several types of threads differing to large degree in their elasticity. Comparative theoretical and experimental studies on natural blood vessels, blood vessel prostheses (of traditional threads) and new textile prostheses showed that the last mentioned, as far as their elasticity in concerned, are most close to the requirements and that they have good functional properties.

The effect of Dibunol and Delagil on the course of experimental pancreatitis was studied in experiments in 80 rats and 36 dogs. The intravenous injection of the drugs was shown to decrease lethality of the animals. Control of biochemical parameters has revealed decreased activity of amylase, lipase, trypsin and malonic dialdehyde, normalized level of superlight luminescence of blood plasma. A good medical effect was obtained in 15 patients with acute pancreatitis.

Experimental investigations (experiments in 61 dogs) have shown the application of drug occlusion on the gland duct system with cryodestruction of necrosis foci to be a promising method for treatment of pancreonecrosis.

The local application of plasma flow to postsurgery wounds in rabbits has revealed accelerated wound healing, reduced perifocal inflammation, the appearance of great numbers of phagocytes and islands of epithelial cells in the wound and certain stimulation of hemopoietic body function. The suppression of free-radical oxidation was accompanied by the activation of the metabolic processes. All this justifies an attempt to apply "plasma methods" in the clinical practice for the treatment of long-healing wounds.

The efficiency of the methods of hypothermia and hyperbaric oxygenation for the preservation of canine hearts was studied. The cardiac function was found to reestablish itself nearly completely after 3 hours of preservation, despite some significant metabolic shifts -- disintegration of oxidation and phosphorylation, activation of lysosomal enzymes, reduction of the store of adenyl macroergs and biogenic amines. Five hours of preservation result in irreversible changes in the heart.

Mathematical analysis was used to compare the antihypoxic action of alpha-tocopherol, inosine and oxidized NAD under long-term extracorporeal circulation. Of the drugs studied, oxidized NAD form was demonstrated to be the most active, inosine appeared less active, and alpha-tocopherol still less active. It is advisable to study more thoroughly the effect of oxidized NAD under long-term extracorporeal circulation.

Gentamicin distribution in biological fluids, organs and tissues, lymph nodes was studied on 70 dogs. Three administration routes were compared: lymphotropic, intramuscular and regional subcutaneous. The lymphotropic route for the drug administration was recommended not long ago. It was shown that the lymphotropic route provided the antibiotic accumulation mainly in some of the abdominal organs as compared to intramuscular administration. Regional lymphotropic administration of the antibiotic to the experimental animals resulted in higher gentamicin levels in the regional lymph nodes and regional organs as compared to the levels observed after the antibiotic regional subcutaneous administration in the same doses.

The experience with modelling acute pancreatitis (AP) in dogs is summarized. In 15 of them, to reproduce AP, the intraductal administration of a bile with trypsin mixture was used, in 8--intraductal administration of automobile under the pressure, in 15--intraparenchymatous administration of automobile at several points. Depending on the method of modelling, the forms, rate and severity of the AP course were different.

The morphological analysis of the state of the heart during hypertermal perfusion with different conservants reveals clear dependence of the microcirculation and the activity of the heart upon the type of the conservant. Perfusion with a salt solution and hemodilution is accompanied by pronounced disorders in microcirculation and unsatisfactory parameters of the cardiac activity. Conservation with cryoprecipitated plasma is characterized by comparatively less microcirculatory disorders, but fails to give a reliable safety of the heart. When using medium 199, changes in microcirculation were found to be minimal and parameters of cardiac activity were satisfactory. In the complex of non-specific changes in microcirculatory vessels the maximum structural lability was revealed in blood capillaries and vessels of the postcapillary-venular link.