Репозиторий Университета

© 2018 EDIZIONI MINERVA MEDICA. BACKGROUND: The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. METHODS: Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum coniugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subiects with a baseline serum coniugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. RESULTS: A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subiects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and y-glutamyltransferase (yGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. As revealed by the recent resurgence of yellow fever virus (YFV) activity in the tropical regions of Africa and South America, YFV control measures need urgent rethinking. Over the last decade, most reported outbreaks occurred in, or eventually reached, areas with low vaccination coverage but that are suitable for virus transmission, with an unprecedented risk of expansion to densely populated territories in Africa, South America and Asia. As reflected in the World Health Organization’s initiative launched in 2017, it is high time to strengthen epidemiological surveillance to monitor accurately viral dissemination, and redefine vaccination recommendation areas. Vector-control and immunisation measures need to be adapted and vaccine manufacturing must be reconciled with an increasing demand. We will have to face more yellow fever (YF) cases in the upcoming years. Hence, improving disease management through the development of efficient treatments will prove most beneficial. Undoubtedly, these developments will require in-depth descriptions of YFV biology at molecular, physiological and ecological levels. This second section of a two-part review describes the current state of knowledge and gaps regarding the molecular biology of YFV, along with an overview of the tools that can be used to manage the disease at the individual, local and global levels.

© 2018 Bissler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction The EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase. Methods For patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015). Results Of the 112 patients who received 1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm3) from baseline was −70.56 (−88.30; −49.64) at time of everolimus discontinuation (n = 11), and −50.55 (−79.40; −23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage. Conclusions Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Human milk provides essential substrates for the optimal growth and development of a breastfed infant. Besides providing nutrients to the infant, human milk also contains metabolites which form an intricate system between maternal lifestyle, such as the mother’s diet and the gut microbiome, and infant outcomes. This study investigates the variation of these human milk metabolites from five different countries. Human milk samples (n = 109) were collected one month postpartum from Australia, Japan, the USA, Norway, and South Africa and were analyzed by nuclear magnetic resonance. The partial least squares discriminant analysis (PLS-DA) showed separation between either maternal countries of origin or ethnicities. Variation between countries in concentration of metabolites, such as 2-oxoglutarate, creatine, and glutamine, in human milk, between countries, could provide insights into problems, such as mastitis and/or impaired functions of the mammary glands. Several important markers of milk production, such as lactose, betaine, creatine, glutamate, and glutamine, showed good correlation between each metabolite. This work highlights the importance of milk metabolites with respect to maternal lifestyle and the environment, and also provides the framework for future breastfeeding and microbiome studies in a global context.

© 2018 Elsevier Inc. Background: Corticotrophin-releasing hormone receptor-1 gene (CRHR1) variants have been implicated in mental health. However, little is known of the effects of CRHR1 on long-term mental health and behavior in presence of environmental stressors. We assess the effects of CRHR1 variant (rs17689918)-by-environment interactions on emotionality and behavioral traits, including anxiety, depression, aggression and antisocial behaviors. We also determine effects of rs17689918-by-environment-by-sex interactions on the above-mentioned outcomes. Methods: Genotypic assessments were carried out in 564 children (mean age 10 years, 52.5% females) from the ongoing longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). Information on stressful life events and family relationships were available at baseline and information on behavioral and mental health outcomes (self- and parent-reports) were available at follow-up ages of 18 and 25 years. ANOVAs were used to determine associations of two-way CRHR1-by-environment and three-way CRHR1-by-sex-by-environment interactions on behavioral and mental health outcomes. Results: Two-way CRHR1 interaction effects showed associations between low familial warmth and hostility in individuals with the GG genotype. Associations of low familial warmth with aggression, of higher number of stressful life events with aggression, and of stressful live events with anxious-depressive symptoms were noted in male A-allele carriers and female GG homozygotes. Conclusion: CRHR1-by-familial environment interactions influence both outwardly-directed aggression as well as mood and anxiety disorder symptoms in a sex-specific manner. The type of environmental stressor can also influence effects of CRHR1 on behavioral and mental health outcomes.

© 2018 Elsevier B.V. Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P-glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED resistance. Presently, there is no consensus on the interaction of carbamazepine (CBZ) with the Pgp. This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid-induced epilepsy. Verapamil significantly increased the anticonvulsant effect of CBZ and reduced its effective dose by at least 30% (from 30 mg/kg to 20 mg/kg). Binding of carbamazepine to the poloxamer 188-coated PLGA nanoparticles enabled a 30-fold increase of its anticonvulsive effect, as compared to the free drug. The inhibition of Pgp did not influence the effectivity of carbamazepine encapsulated in nanoparticles.

© 2018 National Academy of Sciences. All Rights Reserved. Fibrin formation and mechanical stability are essential in thrombosis and hemostasis. To reveal how mechanical load impacts fibrin, we carried out optical trap-based single-molecule forced unbinding experiments. The strength of noncovalent A:a knob-hole bond stabilizing fibrin polymers first increases with tensile force (catch bonds) and then decreases with force when the force exceeds a critical value (slip bonds). To provide the structural basis of catch–slip-bond behavior, we analyzed crystal structures and performed molecular modeling of A:a knob-hole complex. The movable flap (residues γ295 to γ305) containing the weak calcium-binding site γ2 serves as a tension sensor. Flap dissociation from the B domain in the γ-nodule and translocation to knob ‘A’ triggers hole ‘a’ closure, resulting in the increase of binding affinity and prolonged bond lifetimes. The discovery of biphasic kinetics of knob-hole bond rupture is quantitatively explained by using a theory, formulated in terms of structural transitions in the binding pocket between the low-affinity (slip) and high-affinity (catch) states. We provide a general framework to understand the mechanical response of protein pairs capable of tension-induced remodeling of their association interface. Strengthening of the A:a knob-hole bonds at 30- to 40-pN forces might favor formation of nascent fibrin clots subject to hydrodynamic shear in vivo.

© 2018 Elsevier Inc. Oxidative stress is a major contributor to secondary injury signaling cascades following traumatic brain injury (TBI). The role of lipid peroxidation in the pathophysiology of a traumatic insult to neural tissue is increasingly recognized. As the methods to quantify lipid peroxidation have gradually improved, so has the understanding of mechanistic details of lipid peroxidation and related signaling events in the injury pathogenesis. While free-radical mediated, non-enzymatic lipid peroxidation has long been studied, recent advances in redox lipidomics have demonstrated the significant contribution of enzymatic lipid peroxidation to TBI pathogenesis. Complex interactions between inflammation, phospholipid peroxidation, and hydrolysis define the engagement of different cell death programs and the severity of injury and outcome. This review focuses on enzymatic phospholipid peroxidation after TBI, including the mechanism of production, signaling roles in secondary injury pathology, and temporal course of production with respect to inflammatory response. In light of the newly identified phospholipid oxidation mechanisms, we also discuss possible therapeutic targets to improve neurocognitive outcome after TBI. Finally, we discuss current limitations in identifying oxidized phospholipids and possible methodologic improvements that can offer a deeper insight into the region-specific distribution and subcellular localization of phospholipid oxidation after TBI.

© 2018 Wiley-VCH Verlag GmbH  &  Co. KGaA, Weinheim Phosphorolytic transglycosylation catalyzed by nucleoside phosphorylases is an important biotechnological process. The reaction is reversible, and the yield of the target nucleoside depends on its concentration at the equilibrium state. We have shown that initial concentrations of the starting compounds and the phosphorolysis equilibrium constants of starting and final glycosides determine concentrations of all the components at the equilibrium state. Based on that, we developed a novel quantitative approach for the prediction of yields in transglycosylation reactions. This method simplifies the choice of reagent concentrations and their ratios for the maximization of the target nucleoside yield. It is advantageous over widely applied blind and cumbersome trial-and-error approach and can reduce the required chemical and energy resources. The described algorithm could also be applied for other equilibrium transfer reactions. (Figure presented.).

© 2018 Elsevier B.V. A MEMS liquid crystal polymer (LCP), used in the membrane-based pressure sensor, has been found highly useful as a flow sensor. Here we conducted a set of elaborate experiments using an air flow generator to investigate the potential of our LCP flow sensor for sleep apnea therapy. Critical properties of the LCP flow sensor, including flow range, resolution (sensitivity), accuracy, and response time, have been systematically characterized. As a result, LCP flow sensor achieves a limit of detection of 8 LPM to measure flow rate, better than the commercial flow sensor (>10 LPM). Our LCP flow sensor shows a favourable response in a large flow range (8–160 LPM) with a sensitivity of detecting a linear voltage response of 0.004 V per 1 LPM flow rate. With minimum detectable flow, high sensitivity and resolution, we further demonstrated our LCP flow sensor for detecting human respiration. Moreover, using a two- dimensional simulation in COMSOL Multiphysics, we demonstrated the deformation of LCP membrane in response to different flow velocities which leads to resistance change in sensor's strain gauge.

© 2018 Elsevier Ltd and Techna Group S.r.l. Upconversion Sr2(Gd.98-xEr.02Ybx)8Si6O26 (SGSO:2Er3+/xYb3+) phosphor materials were synthesized using a citrate sol-gel process. X-ray diffraction patterns confirmed their hexagonal structure. Field emission scanning electron microscopy images of SGSO:2Er3+/xYb3+ phosphors depicted submicron particles. The enhanced upconversion luminescence properties of SGSO:2Er3+/xYb3+ phosphors were analysed as a function of Yb3+ ion concentration and laser power. The energy transfer induced enhanced emission of the Er3+/ Yb3+ ions co-doped SGSO phosphors was ascribed to multi-phonon relaxation. The calculated chromaticity coordinates of the SGSO:2Er3+/xYb3+ phosphors showed emissions could be tuned by changing Yb3+ ion concentration. Optimized sample exhibited the chromaticity coordinate values near to the ultra-high definition television standard green emission coordinates.

© 2018 American Physical Society. We show that a wide class of layered superconductor-ferromagnet (S/F) hybrids demonstrates the emergence of the Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase well below the superconducting transition temperature. By decreasing the temperature, one can switch the system from uniform to the FFLO state which is accompanied by the damping of the diamagnetic Meissner response down to zero and also by the sign change in the curvature of the current-velocity dependence. Our estimates show that an additional layer of the normal metal (N) covering the ferromagnet substantially softens the conditions required for the predicted FFLO instability, and for existing S/F/N systems, the temperature of the transition into the FFLO phase can reach several kelvins.

© 2018 Kapeleris, Kulasinghe, Warkiani, Vela, Kenny, O'Byrne and Punyadeera. Lung cancer affects over 1. 8 million people worldwide and is the leading cause of cancer related mortality globally. Currently, diagnosis of lung cancer involves a combination of imaging and invasive biopsies to confirm histopathology. Non-invasive diagnostic techniques under investigation include "liquid biopsies" through a simple blood draw to develop predictive and prognostic biomarkers. A better understanding of circulating tumor cell (CTC) dissemination mechanisms offers promising potential for the development of techniques to assist in the diagnosis of lung cancer. Enumeration and characterization of CTCs has the potential to act as a prognostic biomarker and to identify novel drug targets for a precision medicine approach to lung cancer care. This review will focus on the current status of CTCs and their potential diagnostic and prognostic utility in this setting.

© 2018 Pharmascope Publications. All rights reserved. To study the function of the endothelium in conducting vascular pharmacological samples in normal and blocking the synthesis of nitric oxide by ultrasound examination of the velocity of central blood flow in the femoral artery in comparison with the changes in systemic hemodynamics and the linear velocity of microcirculatory flow using laser flowmetry. It was studied the parameters of the blood flow velocity (the maximum systolic and diastolic velocity, average systolic and diastolic velocity, Gosling index of pulsatility and resistance index by the Doppler ultrasound Minimax-Doppler-K), the parameters of central circulation ("Biopac-systems MP-150", AcqKnowledge 4.2, USA), and linear velocity of the microcirculatory flow of the musculus vastus medialis (Biopac MP-150, USA) in intact animals and rats with N-Ni-tro-L-arginine methyl ester (L-NAME) induced deficiency of nitric oxide. Quantitative evaluation of endothelial dysfunction in the conduct of pharmacological tests with endothelium-dependent (acetylcholine) and endothe-lium-independent (sodium nitroprusside) vasodilatation is most indicative in calculating the coefficient reflecting the ratio of vascular responses areas in intact rats with L-NAME induced deficiency of nitric oxide. Blood flow parameters (the maximum systolic velocity, the calculated difference between systolic and diastolic velocities) showed a high correlation, both with mean arterial pressure and a linear velocity of the microcirculatory flow. We conclude, that ultrasound Doppler were reflected in the systemic and local vascular response to the administration of vasodilators. It allows an assessment of endothelial function by using the Minimax-Doppler-K device.

© 2018 IEEE. This presentation will discusses recent studies on two photon polymerization process and examples of its application in TE.

© 2018 IEEE. Authors describe new effect of laser radiation in endoscopic urological surgery (BPH enucleation, en-bloc removal of bladder cancer, stricture endotomy): two-phase jet - a result of superintensive boiling in the area of laser radiation absorption and consisting of steam-gas microbubbles and hot water. In this case, the area of thermal influence appears significantly more, than thickness of a layer in which laser radiation is absorbed. Cutting soft tissue, the jet coagulates section walls due to heat generated at steam condensation. The same jet is formed behind the macrobubble, which is formed in liquid (Moses effect), because of boiling.

© 2018 IEEE. This study aimed to develop the approach to the vasculature formation using LIFT-technology for tissue and organ engineering.

© 2018 IEEE. We have proposed an approach to improve the resolution of terahertz (THz) imaging using the effect of solid immersion - i.e. a reduction in the dimensions of the electromagnetic beam caustic by its formation in a free space, behind the medium possessing high refractive index. We have designed a THz solid immersion lens (SIL) comprised of a polymer wide-aperture aspherical singlet and a crystalline truncated sphere mounted in front of the image plane. We have proposed an approach for the object handling at the focal plane of the THz SIL. We have combined numerical simulations and experimental studies to demonstrate the advanced 0.2λ spatial resolution of the proposed THz SIL - it is beyond the 0.5λ Abbe limit. Finally, we have assembled the continuous-wave THz SIL imaging system and applied it for studying various objects with sub-wavelength variations of structure and dielectric properties.

© 2018 IEEE. We study both theoretically and experimentally an ability for shaping the spectra of the terahertz (THz) pulses, emitted by a photoconductive antennas (PCAs) with the logspiral configuration of electrodes, by impedance matching. We select and fabricate 2 configurations of the LT-GaAs PCAs possessing different frequency-dependent impedances and THz spectra. By comparing the results of our studies, we firstly demonstrate high-to-moderate correlation between the frequency-dependent impedance matching efficiency and the THz spectra. The proposed approach makes possible optimizing the PCA performance for accommodating the needs of the THz technology use in various branches, especially in condensed matter and biomedicine.

© 2018 IEEE. Modern laser technologies have a wide range of scientific, commercial, medical and other applications. In medicine, lasers are used both for diagnostic, therapeutic, and surgical purposes. Safety of laser radiation in assisted reproductive technologies is discussed in the paper. Efficiency of using femtosecond (fs) laser pulses to perform noncontact embryo biopsy as well as laser-assisted hatching is shown. First results on femtosecond laser marking on the surface of embryo outer shell for individual embryo tagging are also presented. Question of safety of THz radiation for living objects (starting at the cellular level and ending with the organism in whole) is still a matter of controversy and requires further study. Experimental study of high-power THz pulses effect on living 2D cell culture is presented. MSC cells are exposed to multiple (from 80 to 100) THz pulses with intensities up to 1 MV/cm. No short-term damage effects are observed during first hours post cell irradiation.