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Manunta P.,Vita-Salute San Raffaele University | Ferrandi M.,CVie Therapeutics Ltd | Cusi D.,Institute of Biomedical Technologies | Ferrari P.,CVie Therapeutics Ltd | And 3 more authors.
Current hypertension reports | Year: 2016

During the past 20 years, the studies on genetics or pharmacogenomics of primary hypertension provided interesting results supporting the role of genetics, but no actionable finding ready to be translated into personalized medicine. Two types of approaches have been applied: a "hypothesis-driven" approach on the candidate genes, coding for proteins involved in the biochemical machinery underlying the regulation of BP, and an "unbiased hypothesis-free" approach with GWAS, based on the randomness principles of frequentist statistics. During the past 10-15 years, the application of the latter has overtaken the application of the former leading to an enlargement of the number of previously unknown candidate loci or genes but without any actionable result for the therapy of hypertension. In the present review, we summarize the results of our hypothesis-driven approach based on studies carried out in rats with genetic hypertension and in humans with essential hypertension at the pre-hypertensive and early hypertensive stages. These studies led to the identification of mutant adducin and endogenous ouabain as candidate genetic-molecular mechanisms in both species. Rostafuroxin has been developed for its ability to selectively correct Na(+) pump abnormalities sustained by the two abovementioned mechanisms and to selectively reduce BP in rats and in humans carrying the gene variants underlying the mutant adducin and endogenous ouabain (EO) effects. A clinical trial is ongoing to substantiate these findings. Future studies should apply both the candidate gene and GWAS approaches to fully exploit the potential of genetics in optimizing the personalized therapy. Source

Cherkasova E.I.,Laboratory | Cherkasova E.I.,Lobachevsky State University of Nizhni Novgorod | Murtazaliyeva M.S.,Volga District Medical Center under Federal Medical and Biological Agency of Russia | Gorshkova T.N.,Volga District Medical Center under Federal Medical and Biological Agency of Russia | And 5 more authors.
Sovremennye Tehnologii v Medicine | Year: 2015

Immortalized cell culture of hepatocytes, Chang liver, is one of the candidates for the use in “bioartificial liver” systems. The aim of the investigation was to evaluate the possibility of using the Chang liver cell culture as a bioreactor cell kit making a complex study of biochemical parameters of its effect on the blood serum of patients with liver diseases of various etiology. Materials and Methods. Samples of blood serum from two groups of patients were investigated: patients with obstructive jaundice were included in group 1 “jaundice” (n=9), group 2 “cirrhosis” (n=10) comprised patients with hepatic cirrhosis and hepatocellular jaundice. To study the effect of the cultured Chang liver cells on the patients’ blood serum, confluent monolayer of the cells was incubated with serum samples at 37°C in a 5% CO2 atmosphere with the ratio of (2.0‒2.1)·105 cells per 0.105 ml of serum during 12 h. On completion of the process, the values of the main biochemical parameters of synthetic (albumin, urea, transthyretin) and detoxifying (total bilirubin fraction) functions were determined, as well as markers of cell destruction (hepatic transaminases, lactate dehydrogenases). Viability cell changes after exposure to the serum were defined by MTT test. Results. It was estimated, that complex assessment of biochemical parameters of synthetic and detoxifying functions of the Chang liver culture relative to the blood serum of the patients of both groups, is the most informative one. This cell culture is synthetically active to the most extent in respect to the serum of the patients in “cirrhosis” group, while in “jaundice” group the reduction of this biochemical parameter was observed. Detoxifying activity of the Chang liver culture, exhibited in the dynamics of bilirubin fractures, was noted in both groups, but in “cirrhosis” group it was most marked, as it occurred in half the cases. Biochemical components of the serum, in their turn, also influenced cell viability. Serum samples of both patient groups were found to inhibit the viability of the cells almost in 50% of cases for each group. Conclusion. The results of complex assessment can be used to determine the efficacy of applying various cell cultures as a model system in the development of “bioartificial liver” systems. Chang liver cell culture, according to the complex assessment results, is most active relative to the blood serum of the “cirrhosis” group of patients with impairments of synthetic and detoxifying liver functions. © 2015, Sovremennye Tehnologii v Medicine. All rights reserved. Source

Sirotkina M.A.,Institute of Biomedical Technologies | Sirotkina M.A.,Nizhny Novgorod State Medical Academy | Buyanova N.L.,Institute of Biomedical Technologies | Buyanova N.L.,Nizhny Novgorod State Medical Academy | And 18 more authors.
Sovremennye Tehnologii v Medicine | Year: 2015

The objective of the research was to study the features of transplantation, growth and visualization of experimental tumors of animals, using multimodal optical coherence tomography (OCT) to develop the methodology of evaluation of individual tumor response to anti-cancer therapy. Materials and Methods. The research was carried out using an experimental high-speed spectral-domain multimodal OCT system developed at the Institute of Applied Physics of the Russian Academy of Sciences (Russia). The technical characteristics of the system are the following: speed of information acquisition, 20,000 А-scans per second; 1.3 μm wavelength; frame size, approximately 4×2 mm; lateral resolution, 25 μm; and depth resolution, 10 μm. We evaluated cross-polarized (CP) and microangiopathic (МА) OCT images. We performed an OCT study of the experimental tumor model of colon adenocarcinoma of mice Colo-26 on BALB/с mice (transplanted by suspension of tumor cells culture) inoculated subcutaneously into the thigh, intradermally into auricle, and in a dorsal skinfold window chamber. In the case of a deep subcutaneous location of a nodule, skin flap over the tumor was surgically opened. CP OCT images were compared with histological preparations (stained using hematoxylin and eosine). Results. It was established that a Colo-26 tumor growing subcutaneously is not suitable with OCT monitoring investigations. Applying of tumor model with opened skin flap made it possible considerably to increase the visualization depth; however, it is not feasible to use this method for everyday OCT monitoring. The tumor grown within a dorsal window chamber is optimal for the visualization of blood vessels by means the OCT. Nevertheless, the inflammation and edema sometimes observed at the tumor site impeded the МА OCT study. Superficial tumors on the auricle are available for OCT investigation throughout their entire depth if the size of nodule does not exceed 1.5 mm. The tumor model on the auricle is convenient for physiological studies of the state of the vessels during the tumor growth. Conclusions. The optimal tumor model for dynamic multimodal OCT observation is a tumor on the auricle. Unlike a tumor located on the thigh it is characterized by a subcutaneous location of the nodule yet one which still remains accessible for visualization. The tumor evolving in the ear can be studied using dynamics which would be impossible for the tumor with opened skin flap. Tumors in the dorsal skin window can also be used for research, but the monitoring of their growth is limited to those that are no larger than 5–7 mm, as the nodule goes beyond the window due to the decreased elasticity of the skin, typical of these mice. © 2015, Sovremennye Tehnologii v Medicine. All rights reserved. Source

Lanari M.,Pediatrics and Neonatology Unit | Vandini S.,University of Bologna | Adorni F.,Institute of Biomedical Technologies | Prinelli F.,Institute of Biomedical Technologies | And 3 more authors.
Respiratory Research | Year: 2015

Background: Tobacco smoke exposure (TSE) is a worldwide health problem and it is considered a risk factor for pregnant women's and children's health, particularly for respiratory morbidity during the first year of life. Few significant birth cohort studies on the effect of prenatal TSE via passive and active maternal smoking on the development of severe bronchiolitis in early childhood have been carried out worldwide. Methods: From November 2009 to December 2012, newborns born at ≥33 weeks of gestational age (wGA) were recruited in a longitudinal multi-center cohort study in Italy to investigate the effects of prenatal and postnatal TSE, among other risk factors, on bronchiolitis hospitalization and/or death during the first year of life. Results: Two thousand two hundred ten newborns enrolled at birth were followed-up during their first year of life. Of these, 120 (5.4 %) were hospitalized for bronchiolitis. No enrolled infants died during the study period. Conclusions: These results confirm the detrimental effects of passive TSE and active heavy smoke during pregnancy for infants' respiratory health, since the exposure significantly increases the risk of hospitalization for bronchiolitis in the first year of life. © 2015 Lanari et al. Source

Ijpma G.,Institute of Biomedical Technologies | Al-Jumaily A.M.,Institute of Biomedical Technologies | Cairns S.P.,Auckland University of Technology | Sieck G.C.,Mayo Medical School
Journal of Applied Physiology | Year: 2011

Length adaptation in airway smooth muscle (ASM) is attributed to reorganization of the cytoskeleton, and in particular the contractile elements. However, a constantly changing lung volume with tidal breathing (hence changing ASM length) is likely to restrict full adaptation of ASM for force generation. There is likely to be continuous length adaptation of ASM between states of incomplete or partial length adaption. We propose a new model that assimilates findings on myosin filament polymerization/ depolymerization, partial length adaptation, isometric force, and shortening velocity to describe this continuous length adaptation process. In this model, the ASM adapts to an optimal force-generating capacity in a repeating cycle of events. Initially the myosin filament, shortened by prior length changes, associates with two longer actin filaments. The actin filaments are located adjacent to the myosin filaments, such that all myosin heads overlap with actin to permit maximal cross-bridge cycling. Since in this model the actin filaments are usually longer than myosin filaments, the excess length of the actin filament is located randomly with respect to the myosin filament. Once activated, the myosin filament elongates by polymerization along the actin filaments, with the growth limited by the overlap of the actin filaments. During relaxation, the myosin filaments dissociate from the actin filaments, and then the cycle repeats. This process causes a gradual adaptation of force and instantaneous adaptation of shortening velocity. Good agreement is found between model simulations and the experimental data depicting the relationship between force development, myosin filament density, or shortening velocity and length. © 2011 by the American Physiological Society. Source

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