Репозиторий Университета

© 2019 Elsevier Ltd The widespread application of laser devices requires development of new protections against light pulses of high intensity. This problem is relevant because of the danger of hitting the civil aviation pilots with bright and powerful radiation originating from the laser sources which are widely used in the everyday life. Therefore, this work is devoted to continuing our research on a new class of macroheterocyclic compounds – thermally and chemically stable J-type phthalocyanine dimers as potential nonlinear absorbers for optical limiting technology. The dimeric complexes of magnesium (1a) and zinc (1b) were covalently bonded to single-walled carbon nanotubes (SWCNTs) to improve the overall characteristics of the potential optical limiters 2a,b as compared to the previously studied corresponding dyes in solutions. The conjugates obtained were investigated using atomic force microscopy (AFM), as well as Raman and IR spectroscopy to confirm formation of the covalent binding of phthalocyanine macrocycles with the carbon surface. Open-aperture Z-scan and a fixed limiter location experiments have demonstrated low values of the limiting threshold and high degree of attenuation of the input laser radiation with the pulses duration located in the nanosecond range.

The article analyzes the indicators of population reproduction on the example of the Kostroma region, presents the dynamics of the main medical and demographic indicators of the region: age structure of the population, mortality, fertility, migration, marriage and divorce rates, as well as the starting positions for overcoming reproductive and demographic disadvantages.

© 2019 Society for Vascular Surgery Objective: This study aimed to evaluate the impact of gravity, reservoir size, and competence of the ostial valve on venous reflux in different body positions. Methods: Our study included 61 lower limbs with primary incompetence of the great saphenous vein (GSV). The diameter of the GSV and its cross-sectional area, time-averaged mean velocity (TAMEAN), and reflux time (RT) were measured with duplex ultrasound with pulsed wave Doppler. Reflux volume (RV) and reflux volume flow rate (Q) were calculated. The measurements were carried out in three body positions: horizontal, A; seated upright with stretched legs, B; and vertical, C. Distal automatic cuff compression-decompression (120 mm Hg) was used as a provocation maneuver. Results: There was 100% occurrence of reflux in the patient positions B and C. Reflux was observed in 91.8% of cases in position A. All reflux parameters (TAMEAN, RT, Q, RV) and the size of the vein were significantly different in the three studied positions. The patient's height did not influence the magnitude of change in reflux parameters. All reflux parameters increased more significantly when the position changed from A to B than from B to C (TAMEAN, +103% and +37%; GSV diameter, +33% and +5%; RV, +408% and +65%, respectively). Conclusions: Observed positional changes in reflux parameters suggest that gravitational forces are not a sole explanation for reflux flow in incompetent GSV. It is likely that the gravitational effect on venous flow is mediated by the changes in vein diameter and the total volume of the venous reservoir of the leg.

© 2019, European Society of Radiology. Objectives: Invasive treatment of tumors adjacent to large hepatic vessels is a continuous clinical challenge. The primary aim of this study was to examine the feasibility of ablating liver tissue adjacent to large hepatic and portal veins with magnetic resonance imaging–guided high-intensity focused ultrasound (MRgHIFU). The secondary aim was to compare sonication data for ablations performed adjacent to hepatic veins (HV) versus portal veins (PV). Materials and methods: MRgHIFU ablations were performed in six male land swine under general anesthesia. Ablation cells of either 4 or 8 mm diameter were planned in clusters (two/animal) adjacent either to HV (n = 6) or to PV (n = 6), with diameter ≥ 5 mm. Ablations were made using 200 W and 1.2 MHz. Post-procedure evaluation was made on contrast-enhanced MRI (T1w CE-MRI), histopathology, and ablation data from the HIFU system. Results: A total of 153 ablations in 81 cells and 12 clusters were performed. There were visible lesions with non-perfused volumes in all animals on T1w CE-MRI images. Histopathology showed hemorrhage and necrosis in all 12 clusters, with a median shortest distance to vessel wall of 0.4 mm (range 0–2.7 mm). Edema and endothelial swelling were observed without vessel wall rupture. In 8-mm ablations (n = 125), heat sink was detected more often for HV (43%) than for PV (19%; p = 0.04). Conclusions: Ablations yielding coagulative necrosis of liver tissue can be performed adjacent to large hepatic vessels while keeping the vessel walls intact. This indicates that perivascular tumor ablation in the liver is feasible using MRgHIFU. Key Points: • High-intensity focused ultrasound ablation is a non-invasive treatment modality that can be used for treatment of liver tumors. • This study shows that ablations of liver tissue can be performed adjacent to large hepatic vessels in an experimental setting. • Liver tumors close to large vessels can potentially be treated using this modality.

© 2019, Springer Nature B.V. The objective of this study was to determine the impact of polymorphism of CYP3A subfamily isoenzymes (allelic variants of CYP3A4*22 and CYP3A5*3) on the efficacy clopidogrel in patients with an acute coronary syndrome (ACS), who have undergone percutaneous coronary intervention (PCI). Platelet activity was determined on a VerifyNow P2Y12 test system in 81 patients with ACS aged 37–91 who had PCI. The activity of CYP3A4/5 was expressed as the ratio of the concentrations of cortisol and 6β-hydroxycortisol was performed by using high performance liquid chromatography. Genotyping was performed by using real-time polymerase real-time chain reaction. The frequencies for the CYP3A5 gene, rs 776746, were identified as follows: 77 (95.1%)—CC, 4 (4.9%)—CT; the allele frequencies by loci for the CYP3A4, rs rs35599367, were as follows: 78 (96.3%)—GG, 3 (3.7%)—AG. There was no statistically significant genotype-dependent difference between the presence of a minor T and G alleles and the presence of clopidogrel resistance (OR 3.53; 95% CI 0.46–26.94; p = 0.233 and p = 0.443, respectively). The average level of the metabolic relationship (6β-hydroxycortisol/cortisol) between the clopidogrel-resistant group and the normal platelet reactivity group was not statistically significantly different: 3.3 ± 2.8 versus 3.2 ± 3.2; p = 0.947. So, the activity of CYP3A4/5 was not related to platelet aggregation rates in this model. Genotyping and phenotyping CYP3A4\CYP3A5 does not predict the antiplatelet effect of clopidogrel. More extensive research is required to establish their clinical relevance.

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. The superficial femoral artery (SFA) is a typical atherosclerosis-prone site. We aimed to explore whether the tortuosity of the SFA associates with the occurrence of atherosclerosis and investigate how vascular tortuosity influences the characteristics of blood flow. Ten patients diagnosed with atherosclerotic disease in their SFAs while free of systemic atherosclerosis risk factors were enrolled together with ten atherosclerosis-free patients. The tortuosity of each SFA was quantitatively evaluated by calculating the averaged curvature (AC), maximum curvature (MC) and fraction of high curvature (FC) based on the geometrical model reconstructed from medical images. Hemodynamic studies were performed using both geometrically simplified and anatomically realistic models of the SFA to systematically address the hemodynamic effects of vascular tortuosity. Morphological analyses revealed that all curvature indices of the SFA were significantly larger in patients with atherosclerosis than in atherosclerosis-free patients (AC [mm−1]: 0.034 ± 0.016 vs. 0.018 ± 0.006; MC [mm−1]: 0.055 ± 0.023 vs. 0.034 ± 0.008; FC [%]: 22.77 ± 10.22 vs. 11.39 ± 6.82; p < 0.001). Simulations of blood flows in the geometrically simplified SFAs showed that increasing vascular curvature caused a progressive increase in the area ratios of low wall shear stress (LWSA) and high oscillatory shear index (HOSA). Hemodynamic studies on the anatomically realistic SFAs further demonstrated that high-curvature SFAs (n = 10) had overall larger LWSA and HOSA compared with low-curvature SFAs (n = 10) (LWSA [%]: 4.13 ± 1.91 vs. 1.79 ± 1.13, p = 0.009; HOSA [%]: 4.95 ± 1.92 vs. 2.37 ± 1.51, p = 0.007). These results suggest that increased vascular tortuosity augments the severity and distribution of atherosclerosis-promoting flow disturbances in the SFA and may be an independent risk factor for atherosclerosis.

© 2018, SICOT aisbl. Objective: To investigate the effect of knee arthroscopic synovectomy (AS) on the disease activity, quality-of-life (QoL), and the functional status of patients with rheumatoid arthritis (RA). Materials and methods: A retrospective analysis was conducted on the outcomes of AS performed on 138 RA patients; pre-surgery assessments were done using Disease Activity score (DAS 28) and Routine Assessment of Patient Index Data З (RAPID-3) on а multidimensional health-assessment questionnaire for disease activity, EuroQol-5D (EQ-5D) and the Short-Form Medical Outcomes Study (SF-36) for quality of life, and the Health Assessment Questionnaire (HAQ) for functional status. The pain response to SA was measured by а visual analogue score (VAS) and the Knee Society Score (KSS). Results: All parameters assessed in the study showed significant positive changes: the activity of the disease decreased, and patients’ functional status and QoL improved. Conclusion: AS is effective treatment for recurrent synovitis of the knee in RA patients. This technique improves the functional status of patients and their quality of life and reduces the activity of the disease.

© 2019 Elsevier Inc. Asialo-human transferrin (asialo-hTf) is a glycoform of the human serum protein transferrin characterized by the lack of the sialic acid (SA) terminal unit. It is known that glycosylation micro-heterogeneity and the presence of SA are strongly involved in protein functioning and pathophysiological activities. Some hTf glycoforms are valuable biomarkers for the detection of both genetic defects of glycosylation and/or sialoform distribution changes. The detection of the carbohydrate deficient transferrin (CDT) glycoforms is currently a widely employed method for the diagnosis of chronic alcohol abuse. The physiological significance of asialo-hTf is still unclear, despite its important biological implications. The current knowledge suggests that asialo-hTf may be involved in regulation of iron transport and release at the hepatic level, which, consequently, could strongly be affected by alcohol consumption. For these reasons, a deeper understanding of asialo-hTf structure and its physiological role is required, and an improved method of its analysis would favor the detection of both chronic abuse and other habits of alcohol intake and/or misuse. Thus, suitable analytical methods possessing higher sensitivity and specificity in comparison with the currently available techniques are certainly recommended. The present review summarizes the studies on asialo-hTf structure, roles, and detection techniques mainly in relation to its possible use as a potentially additional useful biomarker of alcohol abuse, and underlines its prospective value as a forensic and diagnostic tool.

© 2019, Pleiades Publishing, Inc. Abstract: Genetic engineering is considered as background for crop protection against pest damage by adding new genes inside the grains. Rice, like other cereals is included in gene engineering experiments. The questions about possible gene transfer related to food safety appear. It is important to find any additional genes or fragments in animal tissues after consumption of genetically modified (GM) food. Therefore, in this study, the remaining of CryIA(b) gene and P35 were assessed in the liver of rats fed with GM rice. This work presents an experimental study with the intervention of GM rice feeding by Sprague Dawley rats. Overall, 20 male and 20 female SD rats were fed by pellets made by GM rice in 50% of needed carbohydrate for 90 days. Then, sampling was done from rats liver. DNA extraction was done based on the protocol. The quality and quantity of the extracted DNA was done by agarose gel electrophoresis and spectrophotometry, respectively. Detection of GM genes residues, including CryIA(b), P35, and T35 was done by Polymerase Chain Reaction using specific primer pairs. The results were analyzed by agarose gel electrophoresis alongside with 50 bp DNA ladder. The results were compared with the ones in control groups with feeding by standard pellet of non-modified rice. All amplification tests were done in triplicates. Analysis of the amplification of P35, CryIA(b) and T35 showed no residues inside the liver tissue. The results showed no significant difference in the presence of transgenic gene of cryIA(b), T35, and P35 in the liver tissue between the control and experiment groups. Therefore, this study rejects the possibility of gene settle of GM rice gene residues in liver tissue of the animal model studied.

© 2018 Elsevier Ltd In this review, we describe dielectric properties of biological tissues and liquids in the context of terahertz (THz) biophotonics. We discuss a model of the THz dielectric permittivity of water and water-containing media, which yields analysis of the relaxation and damped resonant molecules modes. We briefly describe modern techniques of THz spectroscopy and imaging employed in biophotonics with a strong emphasize on a THz time-domain spectroscopy. Furthermore, we consider the methods of sub-wavelength resolution THz imaging and the problem of THz wave delivery to hard to access tissues and internal organs. We consider the THz dielectric properties of biological solutions and liquids. Although strong absorption by water molecules prevents THz-waves from penetration of hydrated tissues and probing biological molecules in aqueous solutions, we discuss approaches for overcoming these drawbacks – novel techniques of freezing and temporal dehydration by application of hyperosmotic agents which have a potential for cancer detection. We review recent applications of THz technology in diagnosis of malignancies and aiding histology paying particular attention to the origin of contrast observed between healthy and pathological tissues. We consider recent applications of THz reflectometry in sensing the thinning dynamics of human pre-corneal tear film. Modern modalities of THz imaging, which relies on the concepts of multi-spectral and multi-temporal domains and employing the principles of color vision, phase analysis and tomography are discussed. Novel methods of THz spectra analysis based on machine learning, pattern recognition, chemical imaging and the revealing of the spatial distribution of various substances in a tissue, are analyzed. Advanced thermal model describing biological object irradiated by THz waves and phantoms mimicking the optical properties of tissues at THz frequencies are presented. Finally, application of the high-resolution THz spectroscopy in analytic chemistry, biology and medicine are described.

© 2018 MDPI AG. All rights reserved. Soil fungi are known to contain a rich variety of defense metabolites that allow them to compete with other organisms (fungi, bacteria, nematodes, and insects) and help them occupy more preferential areas at the expense of effective antagonism. These compounds possess antibiotic activity towards a wide range of other microbes, particularly fungi that belong to different taxonomical units. These compounds include peptaibols, which are non-ribosomal synthesized polypeptides containing non-standard amino acid residues (alpha-aminoisobutyric acid mandatory) and some posttranslational modifications. We isolated a novel antibiotic peptide from the culture medium of Emericellopsis alkalina, an alkalophilic strain. This peptide, called emericellipsin A, exhibited a strong antifungal effect against the yeast Candida albicans, the mold fungus Aspergillus Niger, and human pathogen clinical isolates. It also exhibited antimicrobial activity against some Gram-positive and Gram-negative bacteria. Additionally, emericellipsin A showed a significant cytotoxic effect and was highly active against Hep G2 and HeLa tumor cell lines. We used NMR spectroscopy to reveal that this peptaibol is nine amino acid residues long and contains non-standard amino acids. The mode of molecular action of emericellipsin A is most likely associated with its effects on the membranes of cells. Emericellipsin A is rather short peptaibol and could be useful for the development of antifungal, antibacterial, or anti-tumor remedies.

© 2018 by the author. The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to generate free radicals in the peroxidase cycle and (pseudo)hypohalous acids in the halogenation cycle. The major true peroxidases are myeloperoxidase, eosinophil peroxidase and lactoperoxidase. (2) Pseudo-peroxidases perform various important functions in the body, but under the influence of external conditions they can display peroxidase-like activity. As oxidative intermediates, these peroxidases produce not only active heme compounds, but also protein-based tyrosyl radicals. Hemoglobin, myoglobin, cytochrome c/cardiolipin complexes and cytoglobin are considered as pseudo-peroxidases. Peroxidases play an important role in innate immunity and in a number of physiologically important processes like apoptosis and cell signaling. Unfavorable excessive peroxidase activity is implicated in oxidative damage of cells and tissues, thereby initiating the variety of human diseases. Hence, regulation of peroxidase activity is of considerable importance. Since peroxidases differ in structure, properties and location, the mechanisms controlling peroxidase activity and the biological effects of peroxidase products are specific for each hemoprotein. This review summarizes the knowledge about the properties, activities, regulations and biological effects of true and pseudo-peroxidases in order to better understand the mechanisms underlying beneficial and adverse effects of this class of enzymes.

© 2018 by the authors. Objectives: Resin-modified glass ionomer cements (RMGIC) are considered excellent restorative materials with unique therapeutic and anti-cariogenic activity. However, concerns exist regarding the use of polyacrylic acid as a dentine conditioner as it may influence the bonding performance of RMGIC. The aim of this study was to evaluate the effect of different protocols for cycling mechanical stress on the bond durability and interfacial ultramorphology of a modern RMGIC applied to dentine pre-treated with/without polyacrylic acid conditioner (PAA). Methods: The RMGIC was applied onto human dentine specimens prepared with silicon-carbide (SiC) abrasive paper with or without the use of a PAA conditioner. The specimens were immersed in deionised water for 24 h then divided in 3 groups. The first group was cut into matchsticks (crosssectional area of 0.9 mm2) and tested immediately for microtensile bond strength (MTBS). The second was first subjected to load cycling (250,000 cycles; 3 Hz; 70 N) and then cut into matchsticks and tested for MTBS. The third group was subjected to load cycling (250,000 cycles; 3 Hz; 70 N), cut into matchsticks, and then immersed for 8 months storage in artificial saliva (AS); these were finally tested for MTBS. The results were analysed statistically using two-way ANOVA and the Student- Newman-Keuls test (α = 0.05). Fractographic analysis was performed using FE-SEM, while further RMCGIC-bonded dentine specimens were aged as previously described and used for interfacial ultramorphology characterisation (dye nanoleakage) using confocal microscopy. Results: The RMGIC applied onto dentine that received no pre-treatment (10% PAA gel) showed no significant reduction in MTBS after load cycling followed by 8 months of storage in AS (p > 0.05). The RMGIC- dentine interface created in PAA-conditioned SiC-abraded dentine specimens showed no sign of degradation, but with porosities within the bonding interface both after load cycling and after 8 months of storage in AS. Conversely, the RMGIC-dentine interface of the specimens with no PAA pre-treatment showed no sign of porosity within the interface after any of the aging protocols, although some bonded-dentine interfaces presented cohesive cracks within the cement after prolonged AS storage. However, the specimens of this group showed no significant reduction in bond strength (p < 0.05) after 8 months of storage in AS or load cycling (p > 0.05). After prolonged AS storage, the bond strength value attained in RMGIC-dentine specimens created in PAA pretreated dentine were significantly higher than those observed in the specimens created with no PAA pre-treatment in dentine. Conclusions: PAA conditioning of dentine prior to application of RMGIC induces no substantial effect on the bond strength after short-term storage, but its use may increase the risk of collagen degradation at the bonding interface after prolonged aging. Modern RMGIC applied without PAA dentine pre-treatment may have greater therapeutic synergy with saliva during cycle occlusal load, thereby enhancing the remineralisation and protection of the bonding interface.

© 2018, Media Sphera Publishing Group. All rights reserved. Essential arterial hypertension (AH) is one of the main risk factors for the development of cognitive impairment and dementia. Cognitive decline is an early sign of brain damage as a target organ of hypertension, it occurs even in patients with uncomplicated hypertension with minimal duration of disease. Cognitive impairment progresses with increasing age and hypertension duration, as well as in non-controlled AH. In patients with hypertension, the prevalence of emotional disorders — anxiety and depression is also high. In addition to antihypertensive therapy, hypertensive patients need correction of concomitant cognitive and emotional disorders. Rat-gopantenic acid simultaneously corrects both emotional and cognitive impairment, and has a good tolerability profile as well. An analysis of the evidence base of rac-gopantenic acid showed its high efficacy in the treatment of mental disorders and good tolerability along with a positive effect on somatic disorders and results of antihypertensive therapy. Taken together, they enhance adherence to treatment and, consequently, reduce the cardiovascular risk.

© 2018 Elsevier B.V. Cardiolipin (CL) is a unique phospholipid localized almost exclusively within the mitochondrial membranes where it is synthesized. Newly synthesized CL undergoes acyl remodeling to produce CL species enriched with unsaturated acyl groups. Cld1 is the only identified CL-specific phospholipase in yeast and is required to initiate the CL remodeling pathway. In higher eukaryotes, peroxidation of CL, yielding CLOX, has been implicated in the cellular signaling events that initiate apoptosis. CLOX can undergo enzymatic hydrolysis, resulting in the release of lipid mediators with signaling properties. Our previous findings suggested that CLD1 expression is upregulated in response to oxidative stress, and that one of the physiological roles of CL remodeling is to remove peroxidized CL. To exploit the powerful yeast model to study functions of CLD1 in CL peroxidation, we expressed the H. brasiliensis Δ12-desaturase gene in yeast, which then synthesized poly unsaturated fatty acids(PUFAs) that are incorporated into CL species. Using LC-MS based redox phospholipidomics, we identified and quantified the molecular species of CL and other phospholipids in cld1Δ vs. WT cells. Loss of CLD1 led to a dramatic decrease in chronological lifespan, mitochondrial membrane potential, and respiratory capacity; it also resulted in increased levels of mono-hydroperoxy-CLs, particularly among the highly unsaturated CL species, including tetralinoleoyl-CL. In addition, purified Cld1 exhibited a higher affinity for CLOX, and treatment of cells with H2O2 increased CLD1 expression in the logarithmic growth phase. These data suggest that CLD1 expression is required to mitigate oxidative stress. The findings from this study contribute to our overall understanding of CL remodeling and its role in mitigating oxidative stress.

© 2018 Medknow Publications. All rights reserved. 2-Amino-4H-chromene derivatives possess anticancer property proved on different in vivo and in vitro models of malignancies such breast, nasopharyngeal, bladder, ovary carcinomas, astrocytoma, and osteosarcoma. We assumed it might be effective to apply one of the derivatives as promising approach to lung carcinoma treatment.To evaluate how novel 4-Aryl substituted 2-Amino-4H-chromene derivative AX-554 impacts tumor growth and progression, as well as possible mechanisms for anticancer effect development on in vivo patient-derived heterotopic xenograft model of lung carcinoma in mice. This was an experimental in vivo study. 40 nu/nu BALB/c female mice were randomly allocated into four equal groups: Intact, control, reference, and main group. Animals of three latter groups were ingrafted with human-derived lung adenocarcinoma. Antitumor and antimetastatic action of AX-554 novel aminochromone derivative as a substance were studied. Mice survival was registered. Kinase of anaplastic lymphoma (ALK), tubulin Beta-3 (TUBB3), and c-mesenchymal-epithelial transition (MET) concentrations in the prime tumor nodes homogenates were determined by quantitative enzyme-linked immunosorbent assay. Dannet's parametric criterion and the nonparametric exact Fisher test were used. The normality of the distribution was determined using ANOVA. The survival curve was analyzed using Gehan's criterion with the Yates's correction. Aminochromone derivative possesses an inhibitory effect on human lung adenocarcinoma transplanted into nu/nu BALB/c female mice, as well as significant antimetastatic activity. About 50 mg/kg/day AX-554 intragastric course increases animals' life expectancy of more than 3.3 times when compared with the control and induces remission in 60% of cases. The anticancer effect of the derivative is due to anti-ALK-mediated activation of tumor cells apoptosis and suppression TUBB3-dependent cell proliferation.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature.  The polypeptide analgesic compounds APCH3 (a TRPV1 receptor inhibitor) and PT1 (a P 2 X 3 receptor inhibitor) were shown not to act on the cardiovascular system or respiratory system when given either as single or multiple doses in mice. The low molecular weight compound sevanol (an ASIC3 receptor inhibitor) had no effect on the cardiovascular system, but prolonged use for 14 days affected measures of the respiratory system, significantly increasing respiratory rate and peak expiratory flow rate.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

© 2018 Radboud University Medical Center Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.

Copyright © 2018 American Chemical Society. Upconversion nanoparticles (UCNPs) coated with polyethylenimine (PEI) are popular background-free optical contrast probes and efficient drug and gene delivery agents attracting attention in science, industry, and medicine. Their unique optical properties are especially useful for subsurface nanotheranostics applications, in particular, in skin. However, high cytotoxicity of PEI limits safe use of UCNP@PEI, and this represents a major barrier for clinical translation of UCNP@PEI-based technologies. Our study aims to address this problem by exploring additional surface modifications to UCNP@PEI to create less toxic and functional nanotheranostic materials. We designed and synthesized six types of layered polymer coatings that envelop the original UCNP@PEI surface, five of which reduced the cytotoxicity to human skin keratinocytes under acute (24 h) and subacute (120 h) exposure. In parallel, we examined the photoluminescence spectra and lifetime of the surface-modified UCNP@PEI. To quantify their brightness, we developed original methodology to precisely measure the colloidal concentration to normalize the photoluminescence signal using a nondigesting mass spectrometry protocol. Our results, specified for the individual coatings, show that, despite decreasing the cytotoxicity, the external polymer coatings of UCNP@PEI quench the upconversion photoluminescence in biologically relevant aqueous environments. This trade-off between cytotoxicity and brightness for surface-coated UCNPs emphasizes the need for the combined assessment of the viability of normal cells exposed to the nanoparticles and the photophysical properties of postmodification UCNPs. We present an optimized methodology for rational surface design of UCNP@PEI in biologically relevant conditions, which is essential to facilitate the translation of such nanoparticles to the clinical applications.